Thoracic Medicine CGMH, Chiayi
Obstructive Airway Disease ( Asthma & COPD )
黃東榮 MD, PhD, 嘉義長庚醫院 呼吸胸腔科
Obstructive airway diseases CHRONIC. BRONCHITIS
ASTHMA
?
CHRONIC BRONCHIOLITIS
EMPHYSEMA
IRREVERSABLE
REVERSABLE
Thoracic Medicine CGMH, Chiayi
Asthma and COPD Similar clinical presentation? Similar pathophysiology? Similar management?
Thoracic Medicine CGMH, Chiayi
Similar clinical Presentation between Asthma and COPD
Thoracic Medicine CGMH, Chiayi
Episodic bronchospasm (esp. acute exacerbation) Nocturnal variability of airflow limitation Associated symptoms: cough, sputum, wheezing, dyspnea Similar risk factors for acute exacerbation: infections, air-borne stimulants Complication:
Simlilar Pathophysiology between Asthma and COPD
Chronic airway inflammation Airway obstruction Respiratory failure
Thoracic Medicine CGMH, Chiayi
Global INitiative for Asthma, GINA The 1st Edition: 1993, WHO, NIH/NHLBL ⇒ The latest revision December 2006
Revised 2006
Definition Asthma (2006, NIH/NHLBL)
(Global INitiative for Asthma, GINA) • Chronic inflammatory disorder • Many cells and cellular elements • Bronchial hyperresponsiveness (BHR, AHR) • Recurrent episodes of symptoms • Widespread, variable , and often reversible airflow limitation
Pathophysiology: Asthma
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Mechanisms: Asthma Inflammation
Source: Peter J. Barnes, MD
Components of the immune response Antigen processing Cellular immunity Epithelium defense barrier
Neurogenic inflammation
ASM Remodelling
Air pollutants, Chemicals
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• Normal airway • Asthmatic airway
Pathophysiology: Asthma Thoracic Medicine CGMH, Chiayi
Airway remodeling
↑mucous glands
↑extracellular matrix (ECM)
Thickening of basement membrane (BM) Hypertrophy & hyperplasia
Neovascularisation
Global Initiative for Chronic Obstructive Lung Disease
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In collaboration with: National Heart, Lung, and Blood Institute, NIH and World Health Organization Aug, 2005
Definition
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Chronic obstructive pulmonary disease (COPD) (GOLD 2005) A disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.
Pathophysiology: COPD
Thoracic Medicine CGMH, Chiayi
Noxious particles and gases Host factors Anti-oxidants
Lung inflammation
Oxidative stress
Anti-proteinases
Proteinases Repair mechanisms
COPD pathology
CELLULAR MECHANISMS OF COPD Perforin Granzyme B TNF-α
Cigarette smoke
Alveolar macrophage
?
CD8 lymphocyte +
MCP-1
Neutrophil chemotactic factors Cytokines (IL-8) Mediators (LTB4)
Neutrophil PROTEASE INHIBITORS
-
Neutrophil elastase PROTEASES MatrixCathepsins metalloproteinases
Alveolar wall destruction (Emphysema)
Mucus hypersecretion (Chronic bronchitis)
PROTEASE-ANTIPROTEASE IMBALANCE IN COPD
Neutrophil elastase Cathepsins MMP-1, MMP-9, MMP-12 Granzymes, perforins Others……..
α 1-Antitrypsin SLPI Elafin TIMPs
Free Radicals in COPD
Pathophysiology: COPD COPD Airways
Epithelial metaplasia Goblet cell hyperplasia Fibrosis
A Diffuse Small Airway Disease
reversible
irreversible
Pathological Characteristics of COPD Patients Need more time to empty their alveoli Prolonged expiratory phase A large fraction of lung volume retained in the lungs (air-trapping)
Air-Trapping in COPD
Increased A-P diameter Increased Lung volume at end-expiration Flattening diaphragm Decreased contractility of diaphragm
Increased Breathing Work in COPD Inspiratory IRV effort
IRV
IRV
VT
VT VT ERV ERV ERV
Air-Trapping No enough expiratory time to return to ERV
Exercise capacity in COPD 75
n = 41 r = 0.56 p = 0.0002
n = 41 r = 0.66 p < 0.0001
50
FEV1%
FEV1 %
50
25
25
0
75
0
100 200 300 400 500 600 700 Walking Distance (meters)
0 50
60
70
80
90
100
O2 Saturation (end of exercise)
Relation of six-minute walking with pulmonary function and ventilatory drive in patients with airflow limitation Chang Gung Medical J. 2001
Quality of life in COPD COPD bronchospasm Loss of recoil
Airway inflammation
Airway narrowing
Abnormal gas exchange
Hyperinflation
Muscle wasting
Breathlessness
Depression and anxiety
Exercise limitation Disability Social withdrawl
Differential diagnosis Overview: Clinical aspects & lung function
COPD • Affects elderly, especially smokers • Slowly progressive • Partially reversible • AHR: ± • Lung volume: hyperinflation • Diffusion: decrease • Chest X-ray: hyperinflation
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Asthma
≈ 10%
• Affects all ages, including children • Episodic course • Fully reversible • AHR: often + • Lung volume: variable • Diffusion: normal • Chest X-ray: normal
Wheezy bronchitis Adapted from Barnes PJ. Chest 2000;117(suppl):10S
Differential diagnosis Overview: Inflammatory cells and mediators
COPD • Inflammatory cells –Neutrophils –Macrophages –CD8+ cells • Mediators –IL-8 –TNF-a –LTB4
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Asthma
≈ 10%
• Inflammatory cells –Eosinophils –Mast cells –CD4+ –Macrophages –Neutrophils • Mediators –Th2 cytokines –Eotaxin –LTC4-E4
Wheezy bronchitis Adapted from Barnes PJ. Chest 2000;117(suppl):10S
Thoracic Medicine CGMH, Chia-Yi
10/23/08
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10/23/08
Similar Management? between Asthma and COPD
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Oxygen Theophyllines Bronchodilators Corticosteroids Avoidance of inhaled stimulants
Current Therapy for Asthma - GINA
Thoracic Medicine CGMH, Chiayi
Asthma Management and Prevention Program: Five Components 1. Develop Patient/Doctor Partnership 2. Identify and Reduce Exposure to Risk Factors 3. Assess, Treat and Monitor Asthma Revised 2006
4. Manage Asthma Exacerbations 5. Special Considerations
Asthma Management and Prevention Program
Component 1: Develop Patient/Doctor 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
Patient education program in Singapore Prabhakaran et al, Singapore med J. 2006, 47(3):225-31
97 hospitalized patients in one year 30 dropped out
Patient education program in Singapore Prabhakaran et al, Singapore med J. 2006, 47(3):225-31
Patient education program in Singapore Prabhakaran et al, Singapore med J. 2006, 47(3):225-31
Patient education
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Nation-wide campaign:
1980s: New Zealand, Australia, National Asthma Council China: 2001, Easy Asthma mnagement 2002, Breathe Easy Centres Korea: 2003, Korea Asthma Foundation Taiwan: 2003, Asthma Watch; Asthma Grid Web-based net Government support ( 國家高速電腦網路 )
Asthma Management and Prevention Program
Component 2: Identify and Reduce Exposure to Risk Factors
Reduce exposure to indoor allergens
Avoid tobacco smoke
Avoid vehicle emission
Identify irritants in the workplace
Explore role of infections on asthma development, especially in children and young infants
Asthma Management and Prevention Program
Component 2: Identify and Reduce Exposure to Risk Factors
避開或掌控氣喘危險因子
改善生活環境 避免非過敏原的因素
Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor Asthma
Depending on level of asthma control (not severity!), the patient is assigned to one of five treatment steps Treatment is adjusted in a continuous cycle involving: - Assessing Asthma Control - Treating to Achieve Control - Monitoring to Maintain Control
Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor Asthma
評估及監測 : 尖峰流量
10/23/08
( 或尖峰呼氣流速 ; PEF)
Difference in GINA guideline 2006
Levels of Asthma Control Controlled
Partly controlled
(All of the following)
(Any present in any week)
Daytime symptoms
None (2 or less / week)
More than twice / week
Limitations of activities
None
Any
Nocturnal symptoms / awakening
None
Any
Need for rescue / “reliever” treatment
None (2 or less / week)
More than twice / week
Lung function (PEF or FEV1)
Normal
< 80% predicted or personal best (if known) on any day
Exacerbation
None
One or more / year
Characteristic
Uncontrolled
3 or more features of partly controlled asthma present in any week
1 in any week
Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor Asthma
氣喘嚴重度分期
(GINA 1998, 2002,
2006)
嚴重度 重度持續性 中度持續性 30 輕度持續性 20-30
症狀頻率 PEF 白天 夜間 % 最佳值 變異度 % 持續 時常 ≦ 60 ＞ 30 ＞1次/天 ≧1次/週 60-80 ＞ ≧1次/週
＞2次/月
Not essential＜for treatment decision! 1次/天
≧ 80
Asthma Management and Prevention Program
Component 3: Assess, Treat and Monitor Asthma
A stepwise approach
The least possible medication
Traditional methods of healing are not recommended
Severity is no longer used as the basis for treatment decision
Component 3: Assess, Treat and Monitor Asthma
Controller Medications
Inhaled glucocorticosteroids Leukotriene modifiers Long-acting inhaled β2-agonists Theophylline Cromones Long-acting oral β2-agonists Anti-IgE Systemic glucocorticosteroids
Component 3: Assess, Treat and Monitor Asthma
Reliever Medications Rapid-acting inhaled β2-agonists Systemic glucocorticosteroids Anticholinergics Theophylline Short-acting oral β2-agonists
Component 3: Assess, Treat and Monitor Asthma
Allergen-specific Immunotherapy
Greatest benefit in allergic rhinitis
The role in asthma is limited
Specific immunotherapy should be considered only after strict environmental avoidance and pharmacologic intervention, including inhaled glucocorticosteroids, have failed
Perform only by trained physician
Large use of shortacting β2agonists
Combined use of LA-β2 agonists and inhaled corticosteroids Leukotri Inhaled ene corticosteroids modifier Fear of shorts? remodeli acting β2ng agonists
inflammation
bronchospasm 19 75
1980
1 985
1 990
1 995
2000
Bronchodilators
Thoracic Medicine CGMH, Chiayi
Anticholinergic M1 M2 M3
Contraction
Relaxation ↑cAMP AMP SMOOTH MUSCLE CELL
β-agonist
theophylline
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Thoracic Medicine CGMH, Chiayi
(Sears, 1985, 1986)
Thoracic Medicine CGMH, Chiayi
(Pearce, 1995; Sears, 1996)
Glucocorticoids– Mechanism of Action Cell membrane GC molecule
GR Increased expression of: • Anti-inflammatory molecules • β-adrenergic receptors
Decreased expression of proinflammatory molecules (e.g., cytokines, ICAM, VCAM) AP
Gene (DNA) Nucleus GRE © P J Barnes 2005
Corticosteroids
Eosinophil
Numbers (apoptosis)
T-lymphocyte
Mast cell
Macrophage Dendritic cell
Cytokines
Numbers
Cytokines Numbers
Effects of Inhaled Glucocorticoids on Inflammation
Pretreatment E=epithelium; BM=basement membrane Laitinen LA et al. J Allergy Clin Immunol. 1992;90:32
Posttreatment (3 mo) 600 µg budesonide bid
Low-Dose Inhaled Glucocorticoids Rate Ratio for Death From Asthma
Preventing Death From Asthma 2.5 2.0 1.5 1.0 0.5 0.0
0
1
2
3
4
5
6
7
8
9
10
Canisters of Inhaled Glucocorticoids/yr Adapted from Suissa S et al. N Engl J Med. 2000;343:332
11
12
Inhaled Glucocorticoids Reduce Asthma-Related Hospitalizations 8
Relative Risk
7 6
β 2-agonists Total Age 0–17
Inhaled Glucocorticoids Total Age 0–17
5 4 3 2 1 0
None 0–1 1–2 2–3 3–5 5–8 8+
Prescriptions/Person-yr Donahue JG et al. JAMA.1997;277:887
Inhaled Corticosteroids: The mainstay of current treatment for bronchial asthma
Long-actingβ2-agonists 1980s Formoterol: full β2-agonists Salmeterol: partial β2-agonists # Action: > 12 hours
Thoracic Medicine CGMH, Chiayi
Long-actingβ2-agonists
Thoracic Medicine CGMH, Chiayi
Possible anti-inflammatory effects Reduce airway edema Reduce airway sensory nerve activation Increase mucociliary transport Stabilize mast cells and neutrophils (?) Reduce airway smooth muscle responsiveness Potentiate steroid effect
Combination therapy
Complementary effects of long-acting ß2-agonist / corticosteroid combination therapy
LABA
✓ ✓✓ ✓ ✓
Smooth Airway muscle inflammation/ dysfunction remodelling
• Bronchoconstriction • Bronchial hyperreactivity • Hyperplasia • Inflammatory mediator release
• Inflammatory cell infiltration/activation • Mucosal oedema • Cellular proliferation • Epithelial damage • Basement membrane thickening
ICS
✓✓ ✓✓ ✓ ✓ ✓
Symptoms\exacerbations Johnson M. Current Allergy Clin Immunol 2002
21 Century First Revolution Seretide v.s Symbicort
Serial FEV1 after One Week of Treatment with Seretide™, FP, SALM or Placebo Mean change from baseline in serial FEV1 (L) 0.8 0.7 0.6 0.5 0.4
Placebo
Seretide™ 50/250 µg BID
FP 250 µg BID
SALM 50 µg BID
0.3 0.2 0.1 0 – 0.1 Baseline 1
2
3
4
6
Time (hours)
8
10
12
Sharpiro, Am J Respir Crit Care Med 2000
FACET Study : Severe exacerbations
no. / patient / y
1 0.8 0.6 0.4 0.2 0
BUD 200 BUD 200 BUD 800 BUD 800 Formoterol Formoterol Pauwels et al. N Engl J Med 1997
FACET Study : change in am PEF change in PEF (l/min)
40 30
BUD800+F
20
BUD200+F
10 0
BUD800
-10
BUD200
-20
-10
0
10
1 3
6
9
12
Run-in (days) Treatment (days) Treatment (months) Pauwels et al. N Engl J Med 1997
Meta-analysis in Asthma
Sin et al. JAMA 2004
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Xanthines (Theophyllines)
Methylxanthines
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Related to caffeine Used in asthma since 1930 Orally active, slow-releasing preparations Less role? Bronchodilator (10-20 mg/L) Anti-inflammatory (5-10 mg/L)
Mechanisms of action of theophyllines
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Phosphodiesterase (PDE) inhibition Adenosine receptor antagonist Stimulation of catecholamine release Mediator inhibition Inhibition of intracellular calcium release
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Leukotriene modifier
Leukotriene in Asthma From phospholipids via FLAP and 5-LO Pathway irresponsive to steroids LTB4: chemotaxis for leukocytes LTC4, LTD4 (CysLTs)
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Anti-IgE
New Anti-IgE antibody
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Omalizumab (Xolair Genentech, USA / Tanox, Inc., USA / Novartis Pharma AG, Switzerland) reduces
circulating free IgE and the levels of highaffinity IgE receptors on basophils inhibits the early- and late-phase response to allergens, suppresses eosinophilic and T cell inflammation in airways In asthma, reduced corticosteroid dosage while improving peak flows, reducing exacerbations, and improved quality of life. approved by FDA for allergic asthma in 2003. (Reviewed by Chung,
REDUCE
LEVEL OF CONTROL
TREATMENT OF ACTION maintain and find lowest controlling step
partly controlled
consider stepping up to gain control INCREASE
controlled
uncontrolled exacerbation
REDUCE
step up until controlled treat as exacerbation
INCREASE
TREATMENT STEPS
STEP
STEP
STEP
STEP
STEP
1
2
3
4
5
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control Step 1 – As-needed reliever medication Patients with occasional daytime symptoms of short duration A rapid-acting inhaled β2-agonist (SABA) is recommended (Evidence A) When symptoms are more frequent, and/or worsen periodically, patients require regular controller treatment (step 2 or higher)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control Step 2 – Reliever medication plus a single controller A low-dose inhaled glucocorticosteroid (ICS) is recommended as the initial controller treatment for patients of all ages (Evidence A) Alternative controller medications include leukotriene modifiers (Evidence A) appropriate for patients unable/unwilling to use ICS
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Step 3 – Reliever medication plus one or two controllers For adults and adolescents, combine a low-dose ICS with an inhaled LABA either in a combination inhaler device or as separate components (Evidence A) Inhaled LABA must not be used as monotherapy For children < 6 y/o, increase to a medium-dose ICS (Evidence A)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Additional Step 3 Options for Adolescents and Adults
Increase to medium-dose ICS (Evidence A) Low-dose ICS combined with leukotriene modifiers (Evidence A) Low-dose sustained-release theophylline (Evidence B)
Meta-analysis in Asthma
Sin et al. JAMA 2004
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Step 4 – Reliever medication plus two or more controllers
Selection of treatment at Step 4 depends on prior selections at Steps 2 and 3 Where possible, patients not controlled on Step 3 treatments should be referred to a health professional with expertise in the management of asthma
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control Step 4 – Reliever medication plus two or more controllers Medium- or high-dose ICS combined with a LABA (Evidence A) Medium- or high-dose ICS combined with leukotriene modifiers (Evidence A) Low-dose sustained-release theophylline added to medium- or high-dose ICS combined with a LABA (Evidence B)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control Step 5 – Reliever medication plus additional controller options Addition of oral glucocorticosteroids to other controller medications may be effective (Evidence D) but is associated with severe side effects (Evidence A) Addition of anti-IgE treatment improves control of allergic asthma (Evidence A)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Stepping down treatment when asthma is controlled
When controlled on medium- to highdose ICS: 50% dose reduction at 3 month intervals (Evidence B) When controlled on low-dose ICS: switch to once-daily dosing (Evidence A)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Stepping down treatment when asthma is controlled When controlled on combination ICS and LABA, reduce dose of ICS by 50% while continuing the LABA (Evidence B) If control is maintained, reduce to low-dose ICS and stop LABA (Evidence D) If no recurrence of symptoms occur for one year, the controller may be stopped (Evidence D)
Component 3: Assess, Treat and Monitor Asthma
Treating to Achieve Asthma Control
Stepping up treatment in response to loss of control
Combing a rapid and long-acting inhaled β2agonist and an ICS in a single inhaler both as a controller and reliever is effecting in maintaining a high level of asthma control and reduces exacerbations (Evidence A) Doubling the dose of ICS is not effective (Evidence A)
Asthma Management and Prevention Program Component 4: Manage Asthma Exacerbations
Primary therapies for exacerbations: Repetitive administration of rapid-acting inhaled β2-agonist Early introduction of systemic glucocorticosteroids Oxygen supplementation Closely monitor response to treatment with serial measures of lung function
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More about Management for Asthma
Choice of patients ICS in asthma: Smoker vs. non-smoker Figure 2 Mean (95% CI) difference between non-smokers and smokers with asthma in change in morning PEF (l/min) on different doses of inhaled beclomethasone. *p
Tomlinson, J E M et al. Thorax 2005;60:282-287
ICS in asthma: Initial dose
high (>800 µg/day beclomethasone (BDP)); moderate (400-800 µg/day); low (<400 µg/day)
Powell, Thorax. 2004 Dec;59(12):1041-5, systemic review
Difficult Asthma
Adequate medication? Confirmation of diagnosis (false asthma?, drug-induced asthma?) Evaluation of compliance, allergen exposure, stress and secondary gain Evaluation of associated disorders
2. 3. 4. 5. 6.
Difficult Asthma
False asthma, pseudoasthma Vocal cord dysfunction Airway stenosis Bronchiolitis Cardiac asthma Allergic bronchopulmonary aspergillosis
Difficult Asthma Associated Disorders
Respiratory tract infection
Rhinitis or sinusitis
GERD
Associated Disorders Respiratory tract infection and asthma
# Early 70’s: associate respiratory infections with acute exacerbation of asthma
Virus: Rhinovirus, RSV, Influenza, Parainfluenza, Adenovirus, Coronavirus.
Atypical pathogens: Chlamydia, Mycoplasma
# Viral vaccination is justified ?
Associated Disorders
Rhinitis, sinusitis and asthma
25 - 70% 過敏性鼻炎患者有鼻竇炎
40 - 80% 鼻竇炎患者有過敏現象
1920 年代：鼻竇炎可引發氣喘
75 - 80% 氣喘患者有鼻炎
70 - 90% 嚴重氣喘患者有異常鼻竇攝影
治療鼻炎可改善氣喘控制
Associated Disorders Impact of allergic rhinitis on asthma
Bousquet, Clin Exp Allergy. 2005;35:723–727 BMC Pulm Med. 2006; 6(Suppl 1): S4.
Immunotherapy in patients with allergic rhinitis prevents the occurrence of asthma
Polosa et al, Respir Res. 2005; 6(1): 153
Associated Disorders Gastro-esophageal reflux disorder (GERD) and asthma
1892, Willium Osler: big meal => asthma
1962, Kennedy: GERD-related bronchospasm
GERD in asthma: 34-89%
Often attacks at night
Probable mechanism: vagal reflex
Treatment of GERD improved control of asthma
Treatment: long-term pantoprazole Calabrese et al. World J Gastroenterol, 2005, 11(48):7657-60
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The real world
Patient under-assessment of control
Asthma control in practice Asthma control in practice is poor: Only 5% of patients achieve GINA-defined control. Doctors don't follow guidelines, underestimate severity Patients underestimate the severity Guidelines are complex and difficult to follow
Patient under-assessment of control Self-assessment of control: Complete control Well control
% of patients 60 50 40 30 20 10 0
USA
Europe
Asia Pacific
Patients with severe persistent symptoms
Japan
Rabe et al. Eur Respir J 2000; www.asthmainamerica.com; Lai et al. J Allergy Clin Immunol 2003; Adachi et al. Arerugi 2002
Asthma control in practice in Taiwan the prescription patterns of anti-asthmatic medications for children Sun et al, J Formos Med Assoc. 2006, 105(4) 225,537 anti-asthma prescriptions were collected from the National Health Insurance Research Database from January 1, 2002 to March 31, 2002
Asthma control in practice in Taiwan the prescription patterns of anti-asthmatic medications for children Sun et al, J Formos Med Assoc. 2006, 105(4)
Asthma control in practice in Taiwan the prescription patterns of anti-asthmatic medications for children Sun et al, J Formos Med Assoc. 2006, 105(4)
New strategies
Can we do better?
Asthma is a variable disease Undertreatment Excessive rescue use Courses of inhaled/oral steroids
Poor control
Asthma control
Fixed dosing
Optimal control
Overtreatment Unnecessary drug intake Unnecessary drug costs + reliever as needed
Time (months, weeks, days)
Hypothesis: AMD; SMART The right dose of Symbicort® at the right time Asthma worsening
Symbicort® inhalations
Asthma control
Quickly gain control 2 inh. bid
Maintain control 1 inh. bid
Step down to adequate dose that maintains control 4 inh. bid*
1 inh. or bid
2 inh. od
+ reliever as needed *The dosage 4 inh. bid is within the SPC of the monocomponents but outside the current SPC for Symbicort
Time (months, weeks, days) inh. = inhalation(s)
Adjustable maintenance dosing reduced severe exacerbations Number of exacerbations 70 60
p=0.018 p=0.08
50 40
Hospitalisation/ ER visits
30
Oral steroid course
20 10 0 Symbicort® AMD
Symbicort® FD
Seretide™ FD
SUND study: Aalbers R et al. Allergy Clin Immunol Int, 15, Suppl. 1 (2003):49-50
As-needed reliever use Daytime reliever use 3.2 (occasions) 2.8
Symbicort® AMD Symbicort® FD Seretide™ FD
2.4 2.0 1.6 1.2 0.8 -30
-20
-10 0 10 20 Days relative to exacerbation
30 Aalbers R, et al (2003)
Symbicort® adjustable maintenance dosing
more cost-effective Cost (€)
Ställberg B, et al (2003)
500 p<0.001
450 400 350 300 250 200
AMD
Fixed dosing
AMD in asthma: INSPIRE study
INSPIRE study: Partridge et al, BMC Pulm Med. 2006; 6: 13.
AMD in asthma: INSPIRE study
INSPIRE study: Partridge et al, BMC Pulm Med. 2006; 6: 13.
Can we do better?
New strategy: Aim for total control => 2000, GOAL
Gaining Optimal Asthma controL (GOAL) study A 1-year, multicentre, randomised, double-blind, stratified, parallel-group, trial in adults and adolescents, comparing: Seretide (salmeterol-fluticasone propionate) vs. Flixotide (fluticasone propionate)
Dose stepped-up to achieve TOTAL CONTROL (or until maximum dose reached) Conducted between December 2000 and December 2002 Involving 326 sites in 44 countries across 6 continents
GOAL study design Phase I Phase II
Oral prednisolone + SFC 50/500
8-week control assessment 4-week control assessment SFC 50/500 or FP 500
Stratum 3
SFC 50/250 or FP 250
Step 2 SFC 50/500 or FP 500
Step 1 SFC 50/250 or FP 250
Strata 1 & 2
SFC 50/100 or FP 100
5068 3421
Step 3
Step 2
Step 1 Visit Week
1 -4
2 0
3 4
4 12
5 24
6 36
SFC, salmeterol/fluticasone propionate combination; FP, fluticasone propionate
7
8 9 52 56
GSK data on file, 2003
% patients achieving total controlled asthma
Patients can achieve total control regardless of asthma severity Seretide Phase 2 Seretide Phase 1
100 80
FP Phase 2 FP Phase 1
60
50%
* 44%
40%
40
29%
28%
*
16%
20 0
*
Steroid naïve
*p < 0.001 (Phase 1)
Low dose ICS
Moderate dose ICS
Approximately 50% patients achieved Total Control
More patients achieved well controlled asthma with Seretide versus FP % patients achieving well-controlled asthma
Seretide Phase 2 Seretide Phase 1
100 80
78%
*
75%
FP Phase 2
*
FP Phase 1
70% 60%
60
62%
*
47%
40 20 0 Steroid naïve
*p < 0.001 (Phase 1)
Low dose ICS
Moderate dose ICS
Aiming for TOTAL CONTROL reduced exacerbations Mean exacerbation rate per patient per year
Baseline
FP
Baseline
Seretide
* p < 0.01
0.7 0.6 0.5 0.4
0.36 * 0.27
0.3 0.2 0.1 0
0.17 0.12
* 0.07
Steroid naïve (S1)
* 0.12
Low dose ICS (S2)
Moderate dose ICS (S3)
Exacerbations during study defined as requiring either oral steroids or hospitalisation
Seretide achieves better levels of quality of life Seretide Maximum achievable score = 7
AQLQ Score
6.5
FP
*
6.0 5.5
* p < 0.008
5.0 4.5 4.0 B/L 4
12
24 Week
36
48 52
By aiming for TOTAL CONTROL, many more patients achieve WELL CONTROLLED asthma
5%
75%
Assessment of Asthma Control Asthma Control Test (ACT) Asthma Control Questionnaire Asthma Therapy Assessment Questionnaire Asthma Control Scoring System
Copyright © 2007 TAC, All rights reserved. Unauthorized use prohibited.
Copyright © 2007 TAC, All rights reserved. Unauthorized use prohibited.
There is always hope!
New Drugs New New PDE New
steroid bronchodilator ? –IV inhibitor ? immune response modifier: eg. PGI2 analog, anti-TNF-α… Growth factor antagonist Smooth muscle modifier: eg. Bronchial thermoplasty… MMP antagonist Anti-MMP-2 & -9 Anti-ADAM33 protein ?
Vaccination Gene therapy Telemedicine
…
And the next?
Gene therapy
Gene vaccination
Transfer of genes for anti-inflammatory proteins e.g.: IL-10, IL-12, IκB.
Anti-sense oligonucleotides e.g. anti-sense IL-4, IL-5.
Telemedicine
利用輸入所在地 結合當地環境 空氣、氣象資訊 提升氣喘照護品質
Thoracic Medicine CGMH, Chiayi
Management for COPD - GOLD
GOLD Workshop Report, 2005
Four Components of COPD Management
Thoracic Medicine CGMH, Chia-Yi
• Assess and monitor disease • Reduce risk factors • Manage stable COPD ●
Education
●
Pharmacologic
●
Non-pharmacologic
• Manage exacerbations
GOLD Workshop Report
Management:
Assess and monitor disease
Thoracic Medicine CGMH, Chia-Yi
GOLD Workshop Report
Management:
Reduce risk factor
Thoracic Medicine CGMH, Chia-Yi
GOLD Workshop Report
Management:
Manage stable COPD
●
Thoracic Medicine CGMH, Chia-Yi
Education
Health education (Evidence A). All COPD-patients benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of dyspnea and fatigue (Evidence A).
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Pharmacologic
None of the existing medications for COPD has been shown to modify the long-term decline in lung function (Evidence A). Pharmacotherapy is used to decrease symptoms and/or complications.
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Pharmacologic: bronchodilators
Central to the symptomatic management of COPD (Evidence A). Principal bronchodilator: Beta2-agonists, anticholinergics, theophylline, and a combination of these drugs (Evidence A). Long-acting bronchodilators are more convenient. Combining bronchodilators may improve efficacy and decrease the risk of side effects (Evidence A).
Patient-centred outcomes: LABAs versus placebo N
Duration (W eeks)
Medication
Dose (μg)
Rescue
Dyspnea
Exercise
HRQL
Exacerbations
283
16
S
50
↑
-
-
↑
-
Boyd 1997
674
16
S
50
↑
↑
NS
-
NS
Mahler 1999
411
12
S
50
↑
NS
-
↑
↑
Rutten Van Molken 1999
144
12
S
50
-
-
-
NS
-
Van Noord 2000
144
12
S
50
↑
-
-
-
NS
Rennard 2001
405
12
S
50
↑
NS
NS
NS
NS
Chapman 2002
408
24
S
50
NS
-
-
NS
NS
Mahler 2002
691
24
S
50
↑
NS
-
NS
NS
Brusasco 2003
1207
26
S
50
-
↑
-
NS
NS
Calverley 2003
1465
52
S
50
↑
NS
-
NS
↑
Hanania 2003
723
26
S
50
-
↑
-
NS
NS
Dahl 2001
780
12
F
12/24
↑
-
-
↑
NS
Aalbers 2002
687
12
F
4.5/9/18
NS/↑/↑
NS/↑/↑
NS
-
NS
Rossi 2002
854
52
F
12/24
↑
-
-
↑
↑
Szafranski 2003
812
52
F
9
-
-
-
-
NS
Study Jones 1997
versus placebo
Action of anti-cholinergics on Muscarinic receptors Pre-ganglionic nerve Parasympathetic ganglion
Sub-types
ACh M (+) 1
M2(-)
Thoracic Medicine CGMH, Chiayi
Receptor dissociation (T½, h)
Ipratropium
Tiotropium
M1
0.11
14.6
M2
0.03
3.6
M3
0.26
34.7
ACh Airway smooth muscle
M3(+)
Disse et al, 1999
Long-acting anti-cholinergics
Thoracic Medicine CGMH, Chiayi
Beneficial Effects of Tiotropium
Once daily with prolonged bronchodilatation
M1-, M3-receptor specific Maesen, Eur Respir J. 1995; Barnes, Thorax 1998; Disse , Am J Respir Crit Care Med. 1999
Bronchodilator activity of tiotropium in COPD patients
Thoracic Medicine CGMH, Chiayi
Tiotropium 80µg
0.3
Tiotropium 20µg
FEV1(L)
Placebo 0.2
0.1
0
-0.1 0
2
4
6
8
10 12 14 16 18 20 22 24
Time post-administration (hours) Maesen et al, Eur Respir J 1995
Effect of tiotropium on symptom scores in COPD
Thoracic Medicine CGMH, Chiayi
Global evaluation score
6.0 5.6 5.2
Tiotropium (n=276)
4.8
Placebo (n=188)
4.4 4.0 1 8
29
50
Test day
71
92 Casaburi et al, 2000
Tiotropium improves Exercise Endurance Time Placebo (n=91)
Thoracic Medicine CGMH, Chiayi
Tiotropium (n=96) **
11
ET (sec)
*
10
∆ =105 s (21.4%)
∆ =1 min 7 s (13.6%)
9
8 min 12 s
8 -5
0
Baseline *P<0.05, **P<0.01
5
10
15
20
25
30
35
40
45
Day Adapted from O’Donnell DE et al. Eur Respir J (2004)
Number of COPD Exacerbations vs Ipratropium p=0.00 6
1.2
0.96
Number of Events/ Patient Year
1.0
24 %
0.8
0.73
0.6 0.4 0.2 0.0
Ipratropium (n=179)
Tiotropium (n=356)
Improvement in health stautus in COPD with tiotropium
Thoracic Medicine CGMH, Chiayi
Placebo Tiotropium
∆ SGRQ total score
0
-2
-4
* -6
*p<0.05 versus placebo -8
Bateman et al, 2001
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Pharmacologic: corticosteroids
The addition of regular treatment with inhaled glucorticosteroids to bronchodilator treatment is appropriate for symptomatic COPD patients with FEV1<50% predicted (Stage III to IV) and repeated exacerbations (Evidence A) Chronic treatment with systemic glucorticosteroids should be avoided (Evidence A)
ISOLDE study: Exacerbations
n=751 40-75 yrs FEV1 1.3 L
Exacerbations/patient/year (mean)
1.4 1.2
1.32
25
%
1.0 0.99
0.8 0.6 0.4 0.2 0
Placebo M Burge et al: BMJ 2000;320:1297-1303
Fluticasone 1 mg
EUROSCOP – change of FEV1 ∆ FEV1
75 50 25
BUD 400 µg bid
N=1277 FEV1 2.5 l, 77% pred.
FEV1 (ml)
0
-25 -50 -75 -100 -125 -150
Placebo
-175 -200 -225
-6 -3 0 3 6 9 12 15 18 21 24 27 30 33 36
mod. after R Pauwels et al., NEJM 340: 1948, 1999
months
ICS in COPD mortality
DD Sin et al., Thorax 60:992, 2005
Monotherapy in COPD (corticosteroid)
ICS long-term study Copenhagen, Verbo, 1999 EUROSCOPE, Pauwells, 1999 ISLODE, Burge, 2000, BMJ LUNG2, NEJM, 2000 Kiri, AJRCCM, 2005 TORCH, ongoing, 6000 patients
⇒ Effective in treatment of short-term (3-6 mo) and acute exacerbations ⇒ No effect on long-term decline of lung function ⇒ Reduction in risk for rehospitalization or death
Combination therapy in COPD (corticosteroid with long-actingβ2-agonist) Breaking the vicious cycle
Cazzola et al. Chest. 2004 .Vol.126, Iss. 1; pg. 220
Budesonide/formoterol in moderate-severe COPD Comared to monotherapy Reduce severe exacerbation Improve FEV1 (vs budesonide) Improve morning PEF Reduce night-time awakening Reduce SOB (vs budesonide) Reduce use of oral steroids (vs Formoterol) Szafranski, ERJ, 2003
Symbicort Reduces Severe Exacerbations Reduction vs placebo (%) 0
Symbicort
Budesonide
Formoterol –2%
–5 –10 –15
–15%
–20 –25 –30
–24%
*†
*p<0.05 vs placebo † p<0.05 Symbicort vs formoterol
Symbicort improves health-related quality of life (SGRQ Total score) Adjusted mean change from 0 run-in
Symbicort
Budesonide
Formoterol
Placebo
–1 –2 –3 –4
MCID
–5 –6
*
MCID = minimum clinically important difference *p<0.05 vs placebo
Fluticasone/Salmeterol in COPD FEV1 Mean Change in FEV1 (ml)
Placebo
SAL 50
Thoracic Medicine CGMH, Chiayi
FP 500
SFC 50/500
160 120 80 40 0 -40 -80
0 2 4
8
16
24
32
40
52
week TRISTAN, Lancet, 2003
Fluticasone/Salmeterol in COPD number/patient/year
Moderate and/or severe exacerbations 1.5
1.30 1.04
**
1.05
**
1
0.97
*
0.5
0 PLA
* p< 0.001 vs PLA
SAL50
FP500
SFC50/500
** p = 0.003 vs PLA TRISTAN, Lancet, 2003
Fluticasone/Salmeterol in COPD SGRQ PLA
SAL50
FP500
SFC50/500
0 -1 -2 -3 -4
*
-5 -6
* p<0.039 vs PLA and FP TRISTAN, Lancet, 2003
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Pharmacologic: other treatment
α - 1 Antitrypsin augmentation Therapy (C) Antioxidant (B) Immunoregulators (B) Antitussives (D) Respiratory Stimulant (Doxaparm,Almitrine) (D,B) Respiratory Care 2001;46:798-825.
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Non-pharmacologic: O2
The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival (Evidence A).
Thoracic Medicine CGMH, Chia-Yi
10/23/08
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Non-pharmacologic: Rehabilitation
Improves exercise capacity Reduces the intensity of breathlessness Improves quality of life Reduces hospitalizations and hospital stay Reduces anxiety and depression (All evidence A).
GOLD Workshop Report
Management:
Manage stable COPD ●
Thoracic Medicine CGMH, Chia-Yi
Non-pharmacologic: Surgery Bullectomy Lung volume reduction surgery (LVRS) Lung transplantation
GOLD Workshop Report
Four Components of COPD Management
Thoracic Medicine CGMH, Chia-Yi
• Assess and monitor disease • Reduce risk factors • Manage stable COPD ●
Education
●
Pharmacologic
●
Non-pharmacologic
• Manage exacerbations
Common Causes of Acute Exacerbations of COPD Primary Tracheobronchial infection Air pollution Secondary Pneumonia Pulmonary embolism Pneumothorax Rib fractures/chest trauma Inappropriate use of sedatives, narcotics, β-blocking agents Right and/or left heart failure or arrhythmias NHLBI/NIH. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2005.
Infectious Agents in COPD Exacerbations Viruses 30% Influenza Parainfluenza Rhinovirus
Other 10%–25% eg, air pollution
Bacteria 40%–50% H. influenzae S. pneumoniae M. catarrhalis
Atypical bacteria 5%–10% C. pneumoniae
GOLD – COPD severity predicts hospitalisation rate Patients with ≥ 1 hospitalisation because of COPD in 3 yrs (%)
12 10 8 6 4 2 0
GOLD 3/4
GOLD 2
GOLD 1
GOLD 0 Mannino ERJ 2006
AGE
205 patients hospitalized for AECOPD, follow-up for 3 years
Follow-up days
Gunen et al ERJ 2005
Severe exacerbations and mortality in COPD No exacerb. 1-2 exacerb.
>3 exacerb.
JJ Soler-Cataluna et al., Thorax 60:925, 2005
GOLD Workshop Report
Management:
Manage exacerbations The most common causes: infection and air pollution. But, about one-third: cannot be identified (Evidence B). Inhaled bronchodilators, theophylline, and systemic corticosteroids are effective (Evidence A). Patients with airway infection may benefit from antibiotic treatment (Evidence B)
GOLD Workshop Report
Management:
Manage exacerbations Noninvasive intermittent positive pressure ventilation (NIIPPV) (Evidence A). No reliable method to identify high-risk (>90%) in-hospital or 6-mo mortality. Not beneficial (and may be harmful) Mucolytic agents Chest physiotherapy Theophylline
Thoracic Medicine CGMH, Chia-Yi
GOLD, 2005
Management:
Manage stable COPD Stage ALL
Thoracic Medicine CGMH, Chia-Yi
Recommended Treatment • Avoidance of risk factor(s) • Influenza vaccination
0: At Risk I: Mild
• ADD: Short-acting bronchodilator when needed
II: Moderate
• ADD: Regular treatment with one or more longacting bronchodilators • ADD: Rehabilitation
III: Severe
• ADD:Inhaled glucocorticosteroids if repeated exacerbations • ADD: Long-term oxygen therapy if respiratory failure
III: Very Severe
• Consider surgical treatments NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO 2005.
Thoracic Medicine CGMH, Chiayi
COPD as a Systemic Disease
Systemic Inflammation in COPD ? Target organs Respiratory system
Systemic inflammation
Hypothesis Systemic Inflammation
Man SF,. et al. Proc Am Thorac Soc 2005, 2, 78-82
Systemic Effects of COPD Systemic inflammation
Oxidative stress Activated inflammatory cells Increased plasma levels of cytokines and (neutrophils/lymphocytes) acute phase proteins Nutritional abnormalities and Increasedloss resting energy expenditure weight Abnormal body composition Abnormal amino acid metabolism
Skeletal muscle dysfunction Loss of muscle mass Abnormal structure/function Exercise limitation
Other potential systemic effects Cardiovascular effects Nervous system effects Osteoskeletal effects
Eur Respir J 2003; 21:347-360
Limb Muscle Increased ventilatory demand
Inactivity Malnutrition Inflammation Intrinsic change Blood flow redistribution To respiratory muscle
Decreased tolerance of Exercise
Mid-thigh size is closely related to survival of COPD patients!
Osteoporosis in COPD Percentage of subject group
No bone loss 100%
13
Osteopenia
Osteoporosis
20
80%
41 32
60%
49
40% 20%
48
55 31
11
0% Healthy subjects n=38
FEV1>50% pred
FEV1<50% pred
n=35
n=46 Bolton et al. AJRCCM 2004
Cardiovascular dysfunction in COPD Abnormal blood gas tension Disruption of pulmonary vascular bed
Endothelial dysfunction
Pulmonary arterial hypertension Cor-pulmonale Abnormal pulmonary mechanics
Increased Blood velocity Change in Blood volume
Increased Cardiac output
TORCH 3-year follow-up Mod-to-severe COPD Lung:35% Cardiovascular:27% Carcinoma:21%
"Mild" COPD – causes of death [%]
50
25 % – 39 %
40 30 20 10 0
COPD
cardiovascular
Lung carcinoma
other
EUROSCOP (n = 18/1277) LUNG HEALTH (n = 149/5887) Postma et al. (n = 22/81) (n = number of deaths/total number) R. A. Pauwels et al., NEJM 1999; 340:1948–1953.; N. R. Anthonisen et al., JAMA 1994; 272:1497–1505; D. S. Postma et al., ARRD 1986; 134:276–280.
COPD Increases the Risk of CV Disease (i.e. Mortality Morbidity)
A, Relationship of CRP and severe airflow obstruction to CIIS (P for trend=0.001)
nteraction of CRP and moderate airflow obstruction to CIIS (P for trend=0.001). Sin, D. D. et al. Circulation 2003;107:1514-1519
Cardiovascular mortality in COPD Marcus 1.93 (1.46,2.52), men
Hole 1.56 (1.26,1.92), men
Hole 1.88 (1.44,2.47), women
Schunemann 2.11 (1.20,3.71), men
Schunemann 1.96 (0.99,3.88), women
Pooled Estimate 1.75 (1.54, 2.01)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Relative Risk of Cardiovascular Mortality (worst FEV1 quintiles vs best FEV1 quintiles
4.0
4.5
Sin et al. Chest 2005
COPD and systemic inflammation COPD studies (n=14) Markers of systemic inflammation
CRP WQ Gan et al., Thorax 59:574, 2004
Sodium and water disturbance in COPD ↑ PaCO2
Protective diuresis
RBF ↓ Effective renal plasma flow ↑Filtration fraction ↑Peritubular oncotic pressure
Dopamine
Dopamine ANP
PRA
↓ PaO2
↑ Tubular Na -H +
+
exchange
↑ Plasma renin activity (PRA)
Digoxin-like substance
↑ Angiotensin II
ANP
Na+ retention Natriuresis oedema
Ang II ↑ Plasma aldosterone ↑ Arginine vasopressin (AVP)
ANP
AVP
ANP
Dopamine
H2O retention oedema
Protective diuresis
Sleep in COPD Polycythaemia
Sleep hypoxaemia In COPD
Hypoventilation
Sleep quality
Combined with Sleep apnoea/hypopnoea syndrome
(SAHS) ↓ FRC
↓ V/Q matching associated with REM ?
COPD 2-4%
SAHS 10%
Anxiety in COPD
Psychosomatic Medicine 65:963-970 (2003) 2% -- 51% Study
Instrument
Participants
Aghanwa et al., 2001 (6)
Clinical evaluation based on ICD-10
Aydin et al., 2001 (7)
Composite international Diagnostic Interview (CIDI) Manifest Anxiety Scale (MAS)
Borak et al., 1998 (15)
Results N = 30 patients with COPD and 30 healthy controls N = 38 COPD patients N = 49 COPD patients
10% of COPD patients met ICD-10 criteria for Generalized Anxiety Disorder compared with 3.3% of health controls 15.8% met DSM-IV criteria for Generalized Anxiety Disorder 49% had high levels of anxiety (scored 7– 10 on MAS); 51% had moderate levels of anxiety (scored 4–6 on MAS) 13% had pathological levels of anxiety (>10 on HAD) 16% had some anxiety disorder; 8% had panic disorder 32.6% had moderate to severe anxiety (BAI > 15) COPD patients had higher on STAI than patients with heart disease, cancer, and other medical problems 2% had moderate anxiety (>2 SD above mean on STAI); 13% had mild anxiety (1–2 SD above mean on STAI)
Engtrom et al., 1996 (16) Karajgi et al., 1990 (10) Kim et al., 2000 (17)
Hospital Anxiety and Depression Scale (HADS) Structured Clinical Interview for DSM-III-R (SCID) Beck Anxiety Inventory (BAI)
N = 68 COPD patients
Kvaal et al., 2001 (20)
State-Trait Anxiety Inventory (STAI)
N = 98 geriatric patients, including 17 with COPD
Light et al., 1985 (21)
State-Trait Anxiety Inventory (STAI)
N = 45 COPD patients
Moore & Zebb, 1999 (12)
Panic Attack Questionnaire-Revised; Anxiety Disorders Interview Schedule-IV modified for self-report Self-report frequency of panic attacks in last 3 weeks Profile of Moods States (POMS)
N = 28 COPD patients
32% met DSM-IV criteria for panic disorder
N = 48 COPD patients
37% reported a panic attack
N = 985 COPD patients and 25 healthy controls
Hospital Anxiety and Depression Scale (HADS) Clinical psychiatric interview
N = 95 COPD patients
COPD patients scored significantly higher than healthy controls on tension-anxiety scale 29.2% had significant anxiety
Geriatric Mental State Schedule
N = 137 COPD patients
Porzelius et al., 1992 (13) Prigatano et al., 1984 (51) Withers, Rudkin, & White, 1999 (18) Yellowlees et al., 1987 (5) Yohannes, Baldwin, & Connolly, 2000 (19)
N = 50 COPD patients N = 43 COPD patients
N = 50 COPD patients
24% had Panic Disorder; 10% had Generalized Anxiety Disorder 18% were clinically anxious
Systemic Effects of COPD COPD is a systemic disease that affects many organs Extrapulmonary effects have a major impact on quality of life, symptoms and mortality Don’t just treat the lung disease Reference: Chest, 2002; 121 (5) : 127S-130S N Engl J Med , 2004; 350(10): 1005-12
Future for COPD
Thoracic Medicine CGMH, Chiayi
Bronchodilators: Tiotropium, selective PDE-IV inhibitors Mediator antagonists: for LTB4, TNF-α, chemokines Antioxidants Anti-inflammatory drugs: Inhibitors for PDE, NF-κB, adhesion molecule Proteinase inhibitors Mucoregulators Alveolar repair: Retinoic acid, hepatocyte GF. Route of delivery
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