The clinical appraoch for patients with asthma COPD overlap syndrome

1. Asthma and COPD Overlap Syndrome
(ACOS)
Theerasuk Kawamatawong MD, FCCP
Division of Pulmonary and Critical Care Medicine
Department of Medicine
Ramathibodi Hospital Mahidol University

2. What is asthma? What is COPD?
Asthma is a chronic inflammatory
disorder of the airways in which
many cells and cellular elements
play a role and associated with
• Airway hyperresponsiveness
• Recurrent episodes of symptoms
• Widespread and variable
airflow obstruction within the lung
that is reversible in nature
Asthma
COPD is a preventable and
treatable disease
• Exacerbations & co-morbidities
• Characterized by
• Persistent airflow limitation &
progressive
• Associated with an enhanced
chronic inflammatory response
in the airways and the lung to
noxious particles or gases
COPD
Global Initiative for Asthma 2014
Global Initiative for Chronic Obstructive Lung Disease. 2013

3. Inflammatory airway diseases
Obstructive airway diseases
Epithelial Cell
COPD cigarette smokes
Wood smoke (Biomass)
Alveolar Macrophages
CD8 T lymphocytes
(Tck)
Neutrophils
Small airway fibrosis
Alveolar destruction
Epithelial Cell Mast cells
Asthma
(Allergen sensitization)
Bronchial construction
Airway hyper-responsiveness
CD8 T lymphocytes
(Th2) Eosinophils

4. Clinical features distinguished asthma from COPD
For General Practice
Asthma COPD
Onset at any time Onset –mid & late life
Usually non smoke Almost invariable
Cough & phlegm (less common) Productive cough common (CB type)
Dyspnea on effort variable DOE predictable and progressive (m/y)
Nocturnal (common) Nocturnal ( uncommon)
Diurnal variation Little variation in flow
Good response to bronchodilator Response to bronchodilator (15-20%)
BHR to nonspecific agent BHR in minor patients
BD: Bronchodilator BHR: Bronchial hyperresponsiveness

5. Spirometry in obstructive airway diseases
Reversible or not reversible obstruction
FEV1
1 2 3 4 5
Normal
Asthma
(after BD)
Asthma
(before BD)
No plateau after 6 sec Flow
Volume
Normal
Asthma
(after BD)
Asthma
(before BD)
Scoop pattern
(concave of expiratory limb)
Expiratory Spirogram Flow volume loop
Reversibility test with short acting bronchodilator
Volume (L)
Time (s)
12% and 200 ml of FEV1

6. Spirometry for COPD Diagnosis and
Classification of Severity
5
4
3
2
1
1 2 3 4 5 6
Liters
COPD
Normal
FEV1
Seconds
FEV1
FVC
FVC
Subjects FEV1 FVC FEV1 / FVC
Normal 4.150 5.200 0.8
COPD 2.350 3.900 0.6
A post-bronchodilator FEV1/FVC < 0.70 confirms the presence of airflow limitation
GOLD 201

7. Dutch hypothesis
Common cause ?
Common mechanisms
Asthma COPD
British hypothesis
Different causes
Different mechanisms
Asthma COPD
COLD or CNSLD

8. Co-morbidities and life style factors
of real world asthma
Co-morbid disease and life
style factors
Prevalence/ degree of problem among patients with asthma
Rhinitis and rhinosinusitis 24-94% (as measured in range of European and American
studies) 50-100% (lifetime prevalence)
Anxiety and depression 25-50% prevalence in severe and difficult -to –control asthma)
Obesity Prevalence has increases concurrently with that of asthma over
the past decades
GERD Five fold high risk of GERD symptoms in individuals with
asthma
Smoking 15-35% (current smokers, with wide variation)
22-43% (ex-smokers)
Device misuse 70%
Real world ICS adherence 30-40%
David Pride and Jean Bousquet et al Curr Allergy Asthma Rep 2011

9. Lung growth and decline
(Interaction of genetic and environmental factors)
-1 0 1 5 10 15 2 0 25 30 35 40 45 50 55 60 65 70 75 80 85 Age
Environment
(E) TS & Genes
Environment
ETS & Genes
Genre leading to abnormal lung development & lung growth
Asthma COPD
Gene for (allergic)
inflammation
Airway re-modeling
Small airway disease
Gene for
Inflammation
Airway re-modeling
Mucus production
Small airway disease
Emphysema
Environment
(E) TS & Genes
Environment
(E) TS & Genes

10. Case HN 4047696
• ผู้ป่วยชายไทย อายุ 64 ปี อาชีพ ทาธุรกิจส่วนตัว
• มาด้วยอาการไอ มีเสมหะในปอด 2 ปี เหนื่อยมากขึ้น มาได้ 1 ปี
• 30 ปี ก่อนได้รับการวินิจฉัยโรคหืด จากแพทย์ ที่โรงพยาบาลอื่น เคยทาการ
ตรวจสารก่อภูมิแพ้ทางผิวหนัง พบว่าแพ้ไรฝุ่น
• ได้รับการรักษา แต่ไม่สม่าเสมอ มีอาการเหนื่อยเป็นครั้งคราว ใช้ยาขยาย
หลอดลม ชนิดรับประทาน และพ่นแล้วอาการดีขึ้น
• มีประวัติสูบบุหรี่ก้นกรอง 10 pack years เลิกสูบบุหรี่ไป 20 ปี
• มีประวัติมารดา เป็นโรคหืด
• ผู้ป่วยมีอาการคัดจมูกน้ามูกไหล เป็นบางครั้งเวลาสัมผัสกับฝุ่นละออง
• ตรวจร่างกาย พบว่ามี nasal mucosal swelling both noses
• AP chest diameter, expiratory wheeze both lungs

11. Examination patients with rhino-conjunctivitis
Allergic Rhinitis :
co-morbidities
Vasomotor rhinitis:
co-morbidities
Oral candidiasis :
local side effect
Malampatti score (OSAHS)
co-morbidities
Posterior nasal drip or cobble stone
granular pharynx
Allergic rhino-conjunctivitis
Allergic shiners
co-morbidities
Speaker received the permission from patients for presenting these picture for academic purposes

12. Chest film PA and lateral
HN 4047696

13. Paranasal sinus film
HN 4047696

14. การทดสอบสมรรถภาพปอดสไปโรเมตรีย์ (31/3/2014)
PFT
parameter
Predicted
value
Pre-BD Pre-BD%
predicted
Post-BD Post-BD%
predicted
% change
VC 3.79 2.93 77.4% 3.76 99.2% 28.1%
FVC (L) max 3.93 2.93 74.7% 3.76 95.7% 28.1 %
FEV1 2.96 1.05 35.4% 1.31 44.4 25.5 %
FEV1 /FVC 0.36 0.34
FEF 25-75% 3.21 0.35 11% 0.41 13.2% 20.6%
PEFR (L/s) 7.82 3.52 45% 3.71 47% 5.3
Pre-BD: Pre-bronchodilator Post-BD: Post-bronchodilator

15. การทดสอบทางห้องปฏิบัติการ
• CBC Hb 13.3 g/dl, Hct 41%, WBC 7000/mm3, P60% L 25%
Eosinophils 10% Mono 4% Baso 1%
• Specific IgE 147.1 IU/ml (Normal <120 IU/ml)
• Specific IgE positive for D pteronyssinus (0.93 KUA/L)
• Fractional excretion exhaled nitric oxide (FeNO)
118 ppb (Normal <50 ppb in adults)

16. ท่านจะให้การวินิจฉัยว่าผู้ป่วยเป็นโรคอะไร เพราะเหตุผล
• Allergic bronchial asthma
• Asthma with airway remodeling
• COPD (Emphysema)
• COPD (Chronic bronchitis)
• COPD with allergic rhinitis and sinusitis
Asthma COPD overlap syndrome (ACOS)
COPD-asthma overlap syndrome (COAS)
HX diagnosed asthma
FEV1>12% & 200 ml Eo
PFT FEV1/FVC<0.7
Cigarette smoking
CXR hyperinflation
Chronic cough
PNS film, SPT, sIgE

17. High resolution computed tomography of chest

18. High resolution computed tomography of chest

21. Role of lung function in asthma and COPD
Test Asthma COPD
Normal FEV1/FVC
(pre or post BD)
Compatible with asthma diagnosis
(controlled)
Generally not compatible
COPD diagnosis
Low FEV1/FVC
(<0.7 post BD)
Indicates airflow limitation but may
improve on treatment
Required for COPD
diagnosis
FEV1 normal Compatible with asthma diagnosis
(controlled)
Rule out COPD if FEV1/FVC
ratio is normal
FEV1 low A measure in assessment of current
asthma control
Risk factor for asthma exacerbation
Indicator of spirometry
severity
Improvement FEV1
>12% and 200 ml
post BD
Usual at some time in course of
disease, but not when controlled or
when on controllers
Often present but an
asthmatic component
should be considered
Improvement FEV1
>12% and 400 ml
post BD
High probability of asthma or
asthma component
Unusual
21

22. Role of blood test and HRCT in asthma and COPD
Test Asthma COPD
Inflammatory biomarkers and imaging finsings
Blood eosinophilia Support asthma diagnosis May increase during exacerbation
Sputum
inflammatory cell
analysis
Role in differential diagnosis not established in large population
FENO High level supports a diagnosis of
eosinophilic asthma
Usually normal
High resolution CT
scan
Normal or some bronchial wall
thickening
Emphysema can be quantified
Tests for atopy
(specific IgE or skin
prick test)
Modestly increases in probability
of asthma but not essential for
diagnosis
Confirm to background
prevalence
Dose not rule out COPD

23. Role of special lung function in asthma and COPD
Test Asthma COPD
Peak Expiratory
flow rate (PEFR)
Useful in assessing variability, response
to treatment, identifying agents and
trigger (occupational asthma)
Reversibility and therapeutic response
Not useful in diagnosis and
monitoring
Special tests
DLCO Normal or high Often reduced
Arterial blood gas
(ABG)
Normal between exacerbation May be abnormal between
exacerbation
Airway hyper-
responsiveness
Not useful in distinguishing asthma and COPD

24. Airways inflammation and asthma severity
Djukanović Ratko. et al Am J Respir Crit Care Med 2000
Sputum ECPSputum Eo count
74 Asthmatics
22 non-atopic control
Eosinophils(103/g)
10000
1000
100
10
1
4000
1000
100
10
1
ECP(ng/ml)
Control Intermittent Mild
moderate
severe Control Intermittent Mild
moderate
severe
P< 0.001
P< 0.01
P <0.01
P <0.05
P< 0.001
P< 0.001
P< 0.001
P< 0.001

25. Airways Inflammation and level of treatments
Sputum NeutrophilsSputum Eosinophils
Djukanović Ratko. et al Am J Respir Crit Care Med 2000
Eosinophils(103/g)
20000
10000
1000
100
10
1
100000
10000
1000
100
10
Control Low
ICS Mild
mod
High
ICS
severe
Neutrophils(103/g)
OCS- OCS+
severe
Control Low
ICS Mild
to mod
High
ICS
severe
OCS- OCS+
severe
P <0.01
P <0.01
P< 0.001
P< 0.001
P< 0.001
P< 0.001 P< 0.005

26. Numbers of inflammatory cells and mediators
increase as COPD severity progresses
GOLD stage
Cell Type
Percent of Airways with Measurable Cells in small
airways (%) by GOLD Stage
I II III IV
PMNs 67 55 84 100
Macrophages 54 66 73 92
Eosinophils 25 33 29 32
CD4+ 63 87 77 94
CD8+ 85 80 88 98
B cells 7 8 45 37
Hogg JC, et al. N Engl J Med. 2004;350:2645-2653.
% a total number of airway examined
PMN = Polymorphonuclear cells

27. Partial reversible obstructive COPD
Increased FeNO and Sputum Eosinophilia
63.8 2.7 9
26.64.1 pack-y
KCO 62.2 %
66.7 ±3.1 9
23.6 2.7 pack-y
KCO 58.6%
Leonardo M. Fabbri and Alberto Papi et al Am J Respir Crit Care Med 2000
FeNOSputum Eo countRev COPD >12% & 200 ml
Post salbutamol 200 µg
Sputumcellcounts(%)
Neutrophils Eosinophils
Control COPD
Not
Rev
COPD
Rev
Control COPD
Not
Rev
COPD
Rev
100
0
COPD
Rev
COPD
Not
Rev
Control
ExhaledNO(ppb)
61.7.4.5

28. FEV1increaseaftersalbutamol(ml)
FENO (ppb)
250
200
150
100
50
0 10 20 30 40 50
COPD with partial bronchodilator
response to SABA is associated with  exhaled NO
and sputum eosinophilia
Stable COPD with partial bronchodilator response to inhaled albuterol
is associated with increased exhaled NO and sputum eosinophilia
Leonardo M. Fabbri and Alberto Papi et al Am J Respir Crit Care Med 2000

29. Inflammatory cell patterns in sputum
COPD and asthma with fixed obstruction
FEV1 56 3 %
20 pack years
FEV1 56 2 %
5 pack years
FEV1 56 3 % FEV1 56 2 %
Leonardo M. Fabbri and Alberto Papi et al Am J Respir Crit Care Med 2003
FeNOSputum Eo count
25%
15
10
5
0
Sputumeosinophils%
ExhaledNO(ppb)
60
40
20
0
COPD Asthma COPD Asthma

30. Bronchial biopsy EG2+ stain and R-BM
Asthma with fixed obstructionCOPD
Leonardo M. Fabbri and Alberto Papi et al Am J Respir Crit Care Med 2003
EG2+ stain
H&E stain

31. Different phenotypes of fixed chronic airway
obstruction from induced sputum
Maria Laura Bartoli et al Respiration 2009
Asthma COPD
FEV1 46.2 ± 6.9 % vs . 50.9 ± 12.6 %
Age 58.0 ± 10.5 y vs. 71.9 ± 5.7 y
N =45
Asthma COPD
FEV1 46.2 ± 6.9 % vs . 50.9 ± 12.6 %
Age 58.0 ± 10.5 y vs. 71.9 ± 5.7 y
Eosinophils(%)
Asthma CB Emphysema
ECP(pg/ml)
Asthma CB Emphysema
Neutrophils(%)
Asthma CB Emphysema
NE(pg/ml)
Asthma CB Emphysema

32. Neutrophilic asthma vs. COPD
HRCT detected bronchial wall thickness (BWT)
Neurtopilic asthma
65 (10) y, atopy (90%)
Smoke 20 packs
FEV1 62.1%
KCO 97.0%
COPD
68 (7) y atopy (47%)
Smoke 67.5 packs
FEV1 57.6%
KCO 56.5%
Smoker control
62 (12) y atopy (47%)
Smoke 38 packs
FEV1 101 %
KCO 73.1%
All participants n =35
Neutrophilic
Asthma
COPD Smoker
Control
Peter G. Gibson et al. Respir Med 2009
Bronchialwallthicknessscore
10
8
6
4
2
0
Bronchial wall thickness score
FEV1predicted(%)
100 %
80
60
40
20
0

33. Variable reversibility depending on bronchodilator
agent test in COPD
Donohue JF. Therapeutic responses in asthma and COPD. Bronchodilators. Chest. 2004
N=813
Ipatropium only
(n =91)
11.2%Salbutamol only
(n =222)
27.4%
Both
(n =280)
34.6%
Neither
(n =217)
26.8%
FEV1
1 2 3 4 5
Normal
Asthma
(after BD)
Asthma
(before BD)
No plateau after 6 secVolume (L)
Time (s)
Reversibility test
with short acting bronchodilator
12% and 200 ml of FEV1

34. The reproducibility of reversibility defined according
to ATS- ERS criteria
Total % not
reversible
at each visit
Calverley PMA et al. Thorax 2003
Visit 0
Visit 1
Visit 2
ATS criteria FEV1 12 % and 200 ml
PFT every 2 months
58%
62%
59%
664
388 276
290 98 122 154
215 75 48 50 76 46 51 103
Reversible Not reversible

35. Physiologic differences
between asthma and COPD
Physiology Asthma COPD
Elastic recoil Normal Decreased
Diffusion capacity
(DLCO)
Normal or increased Decreased
Lung volume Normal Hyperinflation
Bronchodilator
response
Flow-dominant (FEV1
response)
Volume dependent
(FVC response)
Sciurba FC. Chest 2004; 126: 117-124
Normal Volume dependent
obstruction
Obstruction with
reversibility

36. Flow and volume responses
reversibility testing in mild-severe COPD
Tjard Schermer et al Resp Med 2007
N =2210
FVCChange
FEV1 Change
400 µg salbutamol
800
600
400
300
200
100
0
-100
-200
-100 0 100 200 300 400 500 600 700 800
GOLD 1
GOLD 2
GOLD 3
GOLD 4
Mean values for ∆FEV1 0.180 Liter (SD 0.150)
∆ FVC 0.226 Liter (SD 0.227)

37. Volume (FVC) vs. flow (FEV1) responsiveness in COPD
Tjard Schermer et al Resp Med 2007
FVC responder FEV1responder
N =2210
GOLD stage GOLD stage
I II III IV I II III IV
MeanFVCresponse
MeanFEV1response
Former smoker
Current smoker
Former smoker
Current smoker
250
200
150
100
0
250
200
150
100
0
P 0.97P 0.44
∆ FEV1 decreased as the GOLD stage became more severe
whereas ∆ FVC changed in the opposite direction

38. Parameters Asthma COPD P value
Pre-bronchodilator
FEV1(%Pred) 63+11 62+19 NS
FVC(%Pred) 88+15 86+13 NS
FEV1/FVC 0.6+0.1 0.5+0.1 0.006
Post-bronchodilator
FEV1(%Predicted ) 67+10 66+19 NS
FVC(%Predicted ) 91+15 88+13 NS
FEV1/FVC 0.6+0.1 0.5+0.1 0.006
Body plethysmography
TLC(L) 4.0+0.8 5.0+0.9 <0.001
RV(L) 1.8+0.5 2.1+0.5 0.034
DLCO(%Predicted ) 79+16 78+23 NS
Kco(%Prediected) 109+22 82+21 <0.001
VA/TLC 0.85+0.1 0.83+0.08 NS
Older asthma with fixed obstruction and COPD
(Ramathibodi hospital cohort)
Pornsuriyasak P et al Abstract Eur Respir J 2014
Median total IgE (IU/ml) 124 (24-1530)
Mean exhaled NO (ppb) 67 (16-142)
+ve specific IgE or SPT 10 (40%)

39. Treatment asthma with fixed airflow obstruction
(Ramathibodi hospital cohort)
Clinical characteristics
Asthma with fixed
obstruction
(N=25)
COPD
(N=22)
P value
Sex (M/F), N 4/21 21/1 <0.001
Age (years) 69±6 73±7 0.031
BMI(kg/m2) 24±4 22±4 NS
Duration of being diagnosed (y)* 14(2-60) 2(1-11) <0.001
Smoking (pack-years)* 0(0-8) 17(10-120) <0.001
ICS treatment, n (%) 25 (100) 16 (72) 0.005
ICS/LABA treatment, n (%) 24 (96) 14 (63) 0.005
Montelukast treatment, n (%) 14 (56) 1 (4.5) <0.001
LAMA treatment, n (%) 5 (20) 18 (82) <0.001
Pornsuriyasak et al Abstract Eur Respir J 2014

40. Comparing serum inflammatory markers
between COPD with/without chronic bronchitis
Parameters COPD without chronic
bronchitis(n=64)
COPD with chronic
bronchitis(n=57)
P value
White blood cell counts 7035 (median) 7280 (median) 0.34
Serum fibrinogen (mg/dl) 332.73 (103.73) 351.09 (107.9) 0.34
Serum highly sensitive
C-reactive protein (hsCRP)
mg/ml
1.5 (median) 2.5 (median) 0.17
Eosinophil counts (cells/mm3) 228.5 (0-1780) 246.7 (0-1437) 0.87
Independent t-test for comparing mean
Rank sum test for nonparametric
Lueprasitsakul K et al Abstract Eur Resp J 2014

41. ท่านจะให้การรักษาผู้ป่วยโดยการใช้ยาอย่างไร
• Inhaled short acting bronchodilator (prn or regular)
• Inhaled corticosteroid
• Inhaled corticosteroid and long acting B2 agonist
• Inhaled long acting anti-muscarinic
• Combined inhaled long acting anti-muscarinic and
long acting B2 agonist
• Inhaled corticosteroid plus LABA and LAMA
• Theophylline and leukotriene receptor antagonist
Pulmonary rehabilitation
Smoking cessation
Vaccination
41

42. GOLD multidimensional assessment of COPD
Risk
(GOLDClassificationofAirflowLimitation)
Risk
(Exacerbationhistory)
> 2
1
0
(C) (D)
(A) (B)
4
3
2
1
Symptoms
(mMRC or CAT score or CCQ)
Patient is now in 1 of 4
categories:
A: Less symptoms, low risk
B: More symtoms, low risk
C: Less symptoms, high risk
D: More Symtoms, high riskk
Combined assessment symptoms and risk
GOLD 2013
mMRC 0-1
CAT < 10
CCQ <1
mMRC > 2
CAT > 10
CCQ ≥1
FEV1≥50%FEV1<50%
CAT score =3+3+2+2+2+2+2+3 =19
MMRC= 1

43. Step 1 Step 2 Step 3 Step 4 Step 5
Asthma education and environmental control
As need rapid acting
B2A
As need rapid acting B2 agonist
Controller option Select one Select one Add 1 or more Add 1 or both
Low dose ICS Low ICS+LABA Medium or high
ICS +LABA
Oral steroid
(low dose)
Anti-LT Medium or high
dose ICS
Anti-LT Anti-IgE
treatment
Low dose ICS
+Anti-LT
SR Theophylline
Low dose ICS + SR
theophylline
Level of control Treatment action
Controlled Maintain and find lowest controlling step
Partly controlled Considered stepping up to gain control
Uncontrolled Step up until controlled
Exacerbation Treat exacerbation
Reduce Increase
ReduceIncrease
Management approach based on control GINA

44. Pharmacologic treatment GOLD 2013
Patient Recommended first choices Alternative choices Other possible choices
A SAMA prn
or
SABA prn
LAMA or
LABA or
SABA and SAMA
Theophylline
B LAMA
or
LABA
LAMA and LABA SABA and/or SAMA or
SAMA or
Theophylline
C ICS + LABA
or
LAMA
LAMA and LABA
LAMA and PDE4-inh.
LABA and PDE4 inh.
SABA and/or SAMA or
SAMA or
Theophylline
D ICS + LABA
and/ or
LAMA
ICS + LABA and LAMA or
ICS+LABA and PDE4-inh. or
LAMA and LABA or
LAMA and PDE4-inh.
Carbocysteine or
SABA and/or SAMA or
SAMA or
Theophylline
GOLD guideline 2013

45. Medications for asthma and COPD
Asthma COPD
Anti-inflammatory drugs
-Corticosteroids
-Anti-leukotriene
-Theophylline
Bronchodilators
-Short and long acting β2-agonits
-Short and long acting anticholinergic
-Theophylline
Bronchodilator
-Short acting β2-agonits
-Short acting anticholinergic
Anti-inflammatory drugs
-corticosteroid
-PDE4 inhibitors
ICS/LABA combination ICS/LABA combination
Anti-immunoglobulin E Mucolytic drugs
Asthma aims of gaining & maintaining control in stepwise approach
Treatment of asthma is characterized by suppress inflammation
COPD aims of preventing disease progression in stepwise approach
Treatment of COPD is characterized by relief of symptoms

46. Different bronchodilator in asthma and COPD
Asthma COPD
Short acting β2 agonist
-Dosed as needed
-tolerance
Short acting β2 agonist s
-Regularly dosed
-No tolerance
Long acting β2 agonist
-Monotherapy associated with increase
frequency of exacerbation
Long acting β2 agonist s
-Monotherapy associated with decrease
frequency of exacerbation
-Little tolerance
Anticholinergics
-Efficacious in acute asthma attack
Anticholinergics
-efficacious in acute and stable disease
HS Nelson et al. Chest. 2006;129(1):15-26

47. ICS/LABA vs. LABA Outcome: Pneumonia
Analysis broken down by ICS/LABA type
Nannini et al. Cochrane Database Syst Rev 2012; 9: CD006829
Study/ subgroup
Combination
n/N
LABA
n/N
Odds ratio
M-H, Random, 95% CI
FLU/SAL
Mahler 2002 2/165 0/160 4.91 (0.23, 103.04)
SCO100470 2/518 4/532 0.51 (0.09, 2.81)
Hanania 2003 0/178 1/177 0.33 (0.01, 8.15)
TRISTAN 7/358 9/372 0.80 (0.30, 2.18)
O’Donnell 2006 0/62 0/59 Not estimable
Kardos 2007 23/507 7/487 3.26 (1.39, 7.67)
TORCH 303/1546 205/1542 1.59 (1.31, 1.93)
Ferguson 2008 29/394 15/388 1.98 (1.04, 3.75)
Anzueto 2009 26/394 10/403 2.78 (1.32, 5.84)
Subtotal (95% CI) 4122 4120 1.75 (1.25, 2.45)
Total events: 392 (Combination), 251 (LABA)
Heterogeneity: Tau2 = 0.06; Chi2 = 10.03, df = 7 (P = .19); I2 =30%
Test for overall effect: Z = 3.23 (P = 0.001)
BUD/FORM
Calverley 2003 8/254 7/255 1.15 (0.41, 3.23)
Tashkin 2008 10/558 5/284 1.02 (0.34, 3.01)
Rennard 2009 37/988 17/495 1.09 (0.61, 1.96)
Subtotal (95% CI) 1800 1034 1.09 (0.69, 1.73)
Total events: 55 (Combination), 29 (LABA)
Heterogeneity: Tau2 = 0.00; Chi2 = 0.03, df = 2 (P = .99); I2 = 0%
Test for overall effect: Z = 0.37 (P = .71)
Total (95% CI) 5922 5154 1.55 [ 1.20, 2.01 ]
Total events: 447 (Combination), 280 (LABA)
Heterogeneity: Tau2 = 0.04; Chi2 = 12.84, df = 10 (P = 0.23); I2 = 22%
Test for overall effect: Z = 3.32 (P = .0009)
Test for subgroup differences: Chi2 = 2.62, df = 1 (P = .11), I2 = 62%
0.01 0.1 1 10 100
Favours
combination
Favours
LABA
Inhaled corticosteroid therapy is associated
with an increased risk of pneumonia.

48.  Regular treatment with inhaled corticosteroids (ICS)
improves symptoms, lung function and quality of life and
reduces frequency of exacerbations for COPD patients
with an FEV1 < 60% predicted.
 Inhaled corticosteroid therapy is associated with an
increased risk of pneumonia.
 Withdrawal from treatment with inhaled corticosteroids
may lead to exacerbations in some patients.
COPD therapeutic Options : Inhaled Corticosteroids
© 2013 Global Initiative for Chronic Obstructive Lung Disease

49. Rationalized Medication Prescribing for COPD
following GOLD in Ramathibodi Hospital
COPD Medications
COPD with post BD
FEV1<50%
(n=25)
COPD with post BD
FEV1≥50%
(n=84)
P value
Age (years) 70.4 (11.2) 71.2 (9.8) 0.71
AECOPD post index
date
20 (80%) 22 (26.1%) <0.05*
Female gender 5 (20) 15 (17.9%) 0.8
SABA-SAMA 25 (100%) 82 (97%) 0.59
ICS-LABA (FSC) 23 (92%) 45 (53.6%) <0.05*
ICS-LABA (BFC) 1( 4%) 6 (7.1%) 0.49
LAMA (Tiotropium) 14 (56%) 26 (31%) 0.03*
Oral xanthine SR 10 (40%) 27 (32.1%) 0.46
Oral B2 agonist 1 (4%) 3 (3.6%) 0.65
Inappropriate
medications
1 (4.0%) 55 (65.5%) <0.05*
Panumatrassamee C at al. Respirology 2014

50. การทดสอบสมรรถภาพปอดสไปโรเมตรีย์ (13/10/2014)
PFT
parameter
Predicted
value
Pre-BD Pre-BD%
predicted
Post-BD Post-BD%
predicted
% change
FVC 3.73 2.89 77.4% 2.92 78.3% 1.2%
FVC (L) max 3.87 2.93 74.7% 3.76 75.6% 1.2 %
FEV1 2.90 1.27 35.4% 1.29 44.4 1.6%
FEV1 /FVC 0.43 0.44
FEF 25-75% 3.16 0.49 15% 0.41 15.8% 1.6%
PEFR (L/s) 7.74 3.48 45% 3.28 42% -5%
Pre-BD: Pre-bronchodilator Post-BD: Post-bronchodilator

51. หลังรักษาด้วย ICS-LABA-LAMA 6 เดือน (13/10/2014)
PFT
parameter
Predicted
value
Pre-BD Pre-BD%
predicted
Post-BD Post-BD%
predicted
% change
FVC 3.73 2.89 77.4% 2.92 78.3% 1.2%
FVC (L) max 3.87 2.93 74.7% 3.76 75.6% 1.2 %
FEV1 2.90 1.27 35.4% 1.29 44.4 1.6%
FEV1 /FVC 0.43 0.44
PFT
parameter
Predicted
value
Pre-BD Pre-BD%
predicted
Post-BD Post-BD%
predicted
% change
VC 3.79 2.93 77.4% 3.76 99.2% 28.1%
FVC (L) max 3.93 2.93 74.7% 3.76 95.7% 28.1 %
FEV1 2.96 1.05 35.4% 1.31 44.4 25.5 %
FEV1 /FVC 0.36 0.34
การทดสอบสมรรถภาพปอดสไปโรเมตรีย์ 31/3/2014
CAT score =3+3+2+2+2+2+2+3 =19 MMRC= 1
CAT score =1+1+1+1+1+1+1+1 =8 MMRC= 1

52. Cluster analysis of asthma
(Severe Asthma Research Project: SARP)
Eugene R. Bleecker at al NHBLI SARP program Am J Respir Crit Care Med 2010
Asthma with fixed airflow obstruction
33%
40% 94%
Baseline FEV1
≥68% < 68%
Max FEV1 Max FEV1
<108%
≥65%<108%
<65%
Age of onset
<40 y ≥ 40 y
Cluster 1 Cluster 2 Cluster 3 Cluster 4 Cluster 5

53. ACOS definition
Asthma with partially reversible
airflow obstruction that is, based on
change in FEV1 with bronchodilators
with or without emphysema or
reduced carbon monoxide diffusing
capacity (DLco) to <80% predicted
Zeki AA, Schivo M, Chan A, Albertson TE, Louie S. The Asthma–COPD overlap syndrome: a common clinical
problem in the elderly. J. Allergy 2011,
COPD with emphysema accompanied
by reversible or partially reversible
airflow obstruction, with or without
environmental allergies or reduced
DLCO

54. Definition of ACOS syndrome
Major criteria
• A physician diagnosis of asthma and COPD in the same patient
• History or evidence of atopy (hay fever, elevated total IgE)
• Age ≥40 years
• Smoking >10 pack-years
• Postbronchodilator FEV1 < 80% predicted and FEV1/FVC < 70%
Minor criteria
• ≥15% increase in FEV1 or ≥12% and ≥200 ml increase in FEV1
postbronchodilator treatment with salbutmol
Samuel Louie, and Amir A Zeki et al Expert Rev. Clin. Pharmacol.2013

55. Diagnostic Criteria of the ACOS That Had
Been Agreed Upon
% agreement in order to be
consider a major criteria
Type of criterion
Very positive bronchodilator test
(increase in FEV1 ≥15% and ≥400 ml
over baseline)
83 Major
Eosinophilia in sputum 78 Major
Personal history of asthma
(history before the age of 40)
78 Major
Personal history of atopy 50 Minor
High total IgE 50 Minor
Positive bronchodilator test
(increase in FEV1 ≥12% and ≥200 ml
over baseline) on 2 or more occasions
39 Minor
Consensus Document on ACOS in COPD
Juan José Soler-Cataluna, Joan B. Soriano et al. Arch Bronconeumol. 2012

56. โรคหืด
Asthma Syndrome
โรคปอดอุดกั้นเรื้อรัง
COPD Syndrome
โรคหืดผสมโรคปอดอุดกั้นเรื้อรัง
Asthma COPD Overlap Syndrome (ACOS)
Atopy
Cigarette smoking
Biomass exposure
Smooth Muscle dysfunction Small Airway inflammation
and repair
ปัจจัยกระตุ้น
Triggers
Bronchoconstriction
Abnormal bronchial hyper-reactivity
Smooth muscle hyperplasia
& hypertrophy
Inflammatory mediator release
Inflammatory cell infiltration
Mucosal edema
Epithelial damage and mucus hyper-secretion
Basement membrane thickening
Inflammatory mediator release
อาการ และการกาเริบฉับพลัน
Symptoms and Exacerbation

57. ACOS prevalence in obstructive airway diseases
treated in different sites
Amir A. Zeki et al. J of Allergy 2011
Asthma COPD
Emphysema
Overlap
Syndrome
Other
43.1
23.3 19.9
13.7
50%
40%
30%
20%
10%
0
NS
**
*

58. Asthma COPD
Emphysema
Overlap
Syndrome
Other
34.2
43.4
15.8
6.6
50%
40%
30%
20%
10%
0
**
*
Types of obstructive airway diseases
in general pulmonary clinic
Asthma COPD
Emphysema
Overlap
Syndrome
Other
52.9
23.4
21.4
50%
40%
30%
20%
10%
0
**
*
1.4
**
Types of obstructive airway diseases
in severe asthma clinic
Amir A. Zeki et al. J of Allergy 2011

59. Age and gender distribution of ACOS
Amir A. Zeki et al. J of Allergy 2011
% with overlap syndrome
40
35
30
25
20
15
10
5
30-39 40-49 50-59 60-69 >70
Age (years)
3.4% 3.4%
17.2%
37.9% 37.9%
70
60
50
40
30
20
10
0
40-49 50-59 60-69 70-79 >80
Age (years)
Male Female
Sariano JB et al Chest 2013
% with overlap syndrome

60. Exacerbation of ACOS vs. isolated COPD
Hardin M. et al. The clinical features of the overlap between COPD and asthma. Respir. Res. 2011
Frequent exacerbation Severe exacerbation
%subjects
50%
40%
30%
20%
10%
0
%subjects
50%
40%
30%
20%
10%
0
COPD and asthma
42.7
COPD and asthma
32.8%
COPD
17.6%
COPD
18%

61. Impact of ACOS syndrome
A C
OS
61

62. Sputum Eo predict ICS responsiveness in
asthma COPD overlap syndrome
PFT values COPD without
asthma (n = 46)
COPD with
asthma (n = 17)
VC (% pred) 92.3 ± 3.1 96.6 ± 3.6
FEV1 (% pred) 47.5 ± 2.8 51.3 ± 3.5
FEV1/FVC (%) 46.1 ± 1.7 50.9 ± 2.9
TLC (% pred) 132.0 ± 3.3 120.6 ± 4.9
RV (% pred) 228.5 ± 9.9 192.8 ± 13.9
RV/TLC (%) 57.0 ± 1.5 51.7 ± 1.9
DLCO (% pred) 56.2 ± 3.5 72.2 ± 5.4**
PaO2 (Torr) 67.7 ± 1.8 75.9 ± 2.7
PaCO2 (Torr) 42.0 ± 0.8 40.4 ± 1.0
Serum total IgE (IU/mL)‡
249.0 ± 99.4 693.1 ± 309.4
Peripheral eosinophil count (/mm3)
207.9 ± 31.7 407.5 ± 81.8*
Sputumeosinophils%
∆ FEV1 Change (ml)
-200 -100 0 100 200 300 400
N =63
Yoshiaki Kitaguchi et al Int J of COPD 2012
COPD with asthma
COPD without asthma

63. กลุ่มอาการ Asthma
(severe)
Asthma and COPD
Overlap Syndrome
COPD
ลักษณะประชากร อายุ > 40 ปี อายุ> 40 ปี (50-65 ปี) อายุ > 65 ปี
ผู้หญิง > ผู้ชาย Varied ผู้ชาย > ผู้หญิง
Nonsmoker
smoke< 5 pack y
Past or current smoker
smoke > 10 pack y
Past or current smoker
smoke > 10 pack y
Atopic present Atopy present No atopy
โรคร่วม
(co-morbidities)
Rhino-sinusitis
Obesity
GERD
Rhinosinusitis
GERD
GERD
CAD
Metabolic syndrome
ปัญหาที่สาคัญ Frequent
exacerbation
Very frequent
exacerbation> COPD
Exacerbation and exercise
intolerance
ลักษณณะทางพยาธิ
สรีรวิทยา
FEV1/FVC <0.7
DLCO normal
FENO > 50 ppb
Sputum eosinophils
≥3%
Exacerbation >3/y
FEV1/FVC <0.7
DLCO normal or low
FENO > 25-50 ppb
Static hyperinflation
Exacerbation >3-5/y
Frequent nocturnal
awakening ≥4 /week
FEV1/FVC <0.7
DLCO <80% predicted
FENO < 25 ppb
Less nocturnal wakening
Exacerbation >2/y when
FEV1< 50% predict
Pulmonary hypertension

64. Positions for COPD treatment
Phenotypic approach
C D
B
A
Exacerbationfrequency
0-1/year>2/year
Emphysematous
phenotype
Asthma/COPD
Phenotype
Chronic bronchitic
phenotype
Treatment of COPD by Clinical Phenotypes
C D
A BAirflowlimitationbyGOLDstage
4
3
2
1
Exacerbationfrequency
>2
1
0
Symptoms (Questionnaire)
M. Miravitlles et al. Eur Respir J. 2013; 41(6)1252-6 2013 Global Initiative for Chronic Obstructive Lung Disease
LABA or LAMA
ICS-LABA
LABA
or LAMA
LABA
or LAMA
Treatment of COPD by Clinical Phenotypes

65. Step 1 Diagnosis Chronic Airway Disease
Do symptoms suggest chronic airway disease?
Yes No
Step 2 Syndromic Diagnosis in Adults
i) Assemble the features for asthma and COPD that best describe the patient
ii) Compare number of features in favor of each diagnosis and selected diagnosis
Feature if present Favors asthma Favors COPD
Age of onset □ Before age 20 years □ After age 40 years
Pattern of symptom □ Variation over minutes, hrs of d
□ Worse during night or early
morning
□ Triggered by exercise, emotions,
dust or exposure to allergens
□ Persistent despite treatment
□ Good and bad days but always
daily symptoms and exertional
dyspnea
□ Chronic cough and sputum
preceded onset of dyspnea,
unrelated to triggers
Lung function □ Record of variable airflow
limitation (spirometry, peak flow)
□ Record of persistent airflow
limitation (post-bronchodilator
FEV1/FVC < 0.7)
consider other diagnosis

66. Step 2 Syndromic Diagnosis in Adults
i) Assemble the features for asthma and COPD that best describe the patient
ii) Compare number of features in favor of each diagnosis and selected diagnosis
Feature if present Favors asthma Favors COPD
PFT b/w symptom □ Normal □ Abnormal
Past history or
family history
□ Previous doctor DX of asthma
□ Family history of asthma, and
other allergic rhinitis or eczema
□ Previous doctor DX of COPD,
chronic bronchitis or emphysema
□ Heavy exposure to a risk factor :
tobacco smoke, biomass fuels
Time course □ No worsening of symptoms over
time. Symptoms vary either
seasonally, or from year to year
□ May improve spontaneously or
have an immediate response to
BD or ICS over wks
□ Symptoms slowly worsening
over time (progressive course
over years)
□ Rapid-acting bronchodilator
treatment provides only
limited relief
Chest X-ray □ Normal □ Severe hyperinflation
Note: these feature best distinguish B/W asthma and COPD.
Several feature (3 or more) for either asthma or COPD suggest that diagnosis .
If there is similar numbers for both asthma and COPD , consider diagnosis of ACOS

67. Step 1 Diagnosis Chronic Airway Disease
Do symptoms suggest chronic airway disease?
Yes
Step 2 Syndromic Diagnosis in Adults
i) Assemble the features for asthma and COPD that best describe the patient
ii) Compare number of features in favor of each diagnosis and selected diagnosis
Diagnosis Asthma Some feature
of asthma
Feature of
both
Some feature of
COPD
COPD
Confidence
in diagnosis
Asthma Possible
asthma
Could be ACOS Possible COPD COPD
Step 3
Perform
spirometry
Post BD FEV1/FVC <0.7Marked reversible
airflow limitation (pre post DB)
or other proof of variable airflow limitation
Step 4 Initial
treatment
Asthma drug
no LABA
mono-Rx
Asthma drugs
no LABA
mono-Rx
ICS and LABA
+/-LAMA
COPD drugs COPD drugs

68. Conclusions
• Whether the asthma-COPD overlap syndrome (ACOS) is a
separate entity or a hybrid point within a spectrum of related
diseases remains to be determined
• Overlap syndrome is clinically relevant with a 20% prevalence
in populations with airway diseases
• ACOS is important in current or former smokers in 5th decade
of life who have partially reversible obstruction &progressive
exercise intolerance not response to asthma treatments
• Treatment of ACOS is extrapolated from guidelines for asthma
or COPD management.

69. Risk factors
Gender
Age
BMI
Infectious (Rhinovirus, influenza,
mycoplasma, chlamydia)
AHR
Smoking
Allergies
Acute exacerbation
Pollution/environmental toxin
In utero or
Early insults
Smoke exposure
Infections
Genetic susceptibility
Incompatible lung growth
Low birth weight
Nutritional deficiency
Obstructive airway disease
Asthma-COPD Overlap Syndrome
(Novel clinical phenotype? Genotype?
Asthma
COPD
± emphysema
Specific treatment (s) beyond that
used for COPD or asthma
Know treatments
Allergen avoidance
ICS, LABA, LAMA
CS, LTRA, 5-LO inhibitor
Mast cell stabilizer
Theophylline
Omalizumab
Bronchial thermoplasty
Know treatments
Smoking cessation
Pulmonary rehabilitation
ICS, LABA, LAMA
CS, Theophylline
Oxygen therapy
Pulmonary rehabilitation
Lung volume reduction surgery
(RVRS) Endoscopic LVRS

70. Obstructive airway diseases in practice
Phenotypic approach: No one size fit all
C D
B
A
Exacerbationfrequency
0-1/year>2/year
Emphysematous
phenotype
Asthma/COPD
(ACOS) Phenotype
Chronic bronchitic
phenotype
Treatment of COPD by Clinical and Imaging Phenotypes
M. Miravitlles et al. Eur Respir J. 2013; 41(6)1252-6