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PULMONARY DISEASE:
K S CHEW
School of Medical Sciences
Universiti Sains Malaysia
FREE DOWNLOAD at:
Malaysian Thoracic Society Website
http://www.mts.org.my/resources.html
DEFINITION
DEFINITION OF COPD
Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;
2 (4):367-70; discussion 71-2.
Examples of Co-morbidities Associated
With COPD
Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;
2 (4):367-70; discussion 71-2.
WHY SYSTEMIC EFFECTS?
Hypothesis
• The tobacco smoke alone causes
oxidative stress
• The pulmonary inflammatory process in
the lung itself is the source of these
systemic inflammation.
• The increased surface expression of
several neutrophil adhesion molecules
may be due to genetic predisposition
Agusti AG. Systemic effects of chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;
2 (4):367-70; discussion 71-2.
DISEASE BURDEN
COPD is projected to be the third
biggest cause of mortality by 2020
1990 2020
Ischaemic heart disease 1st Ischaemic heart disease
Cardiovascular disease 2nd Cardiovascular disease
Lower respiratory infection 3rd COPD
Diarrhoeal disease 4th Lower respiratory infection
Perinatal disorders 5th Lung cancer
COPD 6th Road traffic accident
Tuberculosis 7th Tuberculosis
Measles 8th Stomach cancer
Road traffic accident 9th HIV
Lung cancer 10th Suicide
3.0
1.5
1.0
0.5
0
–59% –64% –35% +163% –7%
1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998 1965 - 1998
Source: NHLBI/NIH/DHHS
Model Projections of Moderate-Severe
COPD in Population Aged ≥ 30 Years
AIRFLOW LIMITATION
Pathogenesis of
COPD
Host factors
Amplifying mechanisms
Anti-proteases
SLPI α1-AT
Proteolysis
↑ Mucus secretion
Source: Peter J. Barnes, MD
Inflammation plays a central role in the
pathogenesis and pathology of COPD
Cigarette smoke
(and other irritants)
Genetic susceptibility
Lung Inflammation
• Inflammatory cells
• Inflammatory mediators
• Oxidative stress
• Proteases
COPD pathology
Obstructive Mucus Alveolar
bronchiolitis hypersecretion wall destruction
Adapted from Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guidelines, 2009. Available from http://www.goldcopd.com/
DIAGNOSIS AND
CLASSIFICATION OF SEVERITY
DIAGNOSIS
Spirometry is essential
for the diagnosis of
COPD and is useful for
assessment of the
severity of airflow
obstruction (Grade C)
• Addition of fluticasone–salmeterol to
tiotropium therapy did not statistically
influence rates of COPD exacerbation but
did improve lung function, quality of life,
and hospitalization rates in patients with
moderate to severe COPD
• Aaron SD et al. Tiotropium in combination with
placebo, salmeterol, or fluticasone–salmeterol for
treatment of chronic obstructive pulmonary
disease. A randomized trial. Ann Intern Med
2007 Feb 19;
Can we give COPD
patients a brighter start
to their day and reduce
their future risk ?
The impact of COPD Exacerbations
1.0 0 exacerbations
1–2 exacerbations
≥ 3 exacerbations
0.8
Survival probability
P < 0.0002
0.6
P < 0.0001
0.4 P = 0.069
0.2
0
0 10 20 30 40 50 60
Time (months)
40
37%
35 34%
30 28%
27%
25%
25
21%
20
17%
16%
15
11%
10 9% 9%
7%
5 4%
0
Morning Mid-day Afternoon Evening Night No particular Difficult to say
time of day
• Washing
• Dressing
• Making breakfast
Partridge MR et al. Current Medical Research and Opinion 2009; 25(8): 2043-2048
COPD patients want faster symptom relief
0 10 20 30 40 50 60
Patients (%)
• Long-acting bronchodilator
• Fast onset within 3-5
hours • Onset as fast as salbutamol
1. Barnes PJ. Scientific rationale for using a single inhaler for asthma control. Eur Respir J. 2007 Mar;29
(3):587-95.
2. Bousquet J, Boulet LP, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A.
Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/
fluticasone. Respir Med. 2007 Dec;101(12):2437-46.
3. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE, Buhl R. Effect of budesonide/
formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007 May;61(5):
725-36.
Formoterol is a full β2-agonist, whereas salmeterol
is a partial β2-agonist.
Therefore, increasing the dose of formoterol in the
presence of ICS is associated with increased
protection from exacerbations.
But higher doses are not recommended with
salmeterol because it has a plateau in its efficacy at
around 100µg/day.
1. Barnes PJ. Scientific rationale for using a single inhaler for asthma control. Eur Respir J. 2007 Mar;29
(3):587-95.
2. Bousquet J, Boulet LP, Peters MJ, Magnussen H, Quiralte J, Martinez-Aguilar NE, Carlsheimer A.
Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/
fluticasone. Respir Med. 2007 Dec;101(12):2437-46.
3. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE, Buhl R. Effect of budesonide/
formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007 May;61(5):
725-36.
ICS upregulates the β2-receptors
Non-bronchodilator effects
◦ Reduced plasma exudation
by relaxes the endothelial cells, thus closes the gap
◦ Mast cell stabilization
◦ Reduced neutrophils
Thus reduce the releases of reactive oxygen species via
the activated neutrophils
1.32 120
Symbicort + tiotropium
Symbicort ® 320/9 µg bid
1.28 P < 0.001
100 P < 0.001
1.16 60
1.08 tiotropium
20
1.04
1.00 0
-1 0 5 10 15 0 5 10 15
0.30
+
0.25
≠
+
0.20
0.15
0.10
0.05
0.00
TOTAL Wash Dry Get Eat Walk early Walk late
SCORE yourself yourself dressed breakfast
Bid = twice daily; CDLM = Capacity of Daily Living During the Morning
+p<0.02 vs salmeterol/fluticasone ≠p<0.05 vs salmeterol/fluticasone
0.35
0.25
p=0.001†
0.20
0.15
p=0.027^
0.10 tiotropium
0.05
0
1 2 3 4 5 6 7 8 9 10 11 12
Weeks
^Treatment comparison from randomisation to first week of treatment
†Treatment comparison from randomisation to last week of treatment
Adapted from Welte et al. Am J Respir Crit Care Med 2009, 180: 741-750
Better symptom relief during the day and night
with Symbicort® *
Mean difference in COPD symptom score from run-in to full treatment period
0.1
Adapted from Welte et al. Am J Respir Crit Care Med 2009, 180: 741-750
Less reliever use with Symbicort® *
Reliever use at run-in and 12 week (last week)
0.160
0.155
0.150
P<0.001
0.145
0.140
0.135
0.130
Run-in Week 12 Run-in Week 12
Daytime Night-time
6
P = 0.023
5
4 3.8
2
1.5
0
SGRQ-C total
Comparisons are from randomisation to last visit
0.3
tiotropium
0.2
Symbicort + tiotropium
0.1
0.0
15 30 45 60 75 90
Days since randomisation
N=660
*Symbicort + tiotropium vs tiotropium alone
Adapted from Welte et al. Am J Respir Crit Care Med 2009, 180: 741-750
65% less Hospitalization/ER treatments
with Symbicort®*
Events/1000 patients/3 months
100
70
60
50
40
30 28
20
10
0.1 1 10 100
Hazard ratio (95% CI) 1. Szafranski W et al. Eur Respir J 2003; 21:74–81,
2. Calverley PM et al. Eur Respir J 2003; 22:912–919,
Control treatment Inhaled budesonide treatment 3. Rennard SI et al. Drugs 2009; 69:549–565,
4. Tashkin DP et al. Drugs 2008; 68:1975–2000,
Data were adjusted for age, sex, smoking status, body mass index and 5. Bourbeau J et al. Am J Respir Crit Care Med 1994; 149(4 Suppl 2):A183,
FEV1 (% predicted) 6. Pauwels RA et al. N Engl J Med 1999; 340:1948–1953,
CI = confidence intervals; SAE = serious adverse event 7. Sin DD et al. Lancet 2009; 374:712–719.
SUMMARY