Asthma and copd overlap syndrome (acos) tst edited ramathibodi

Asthma and COPD Overlap Syndrome

(ACOS)

Theerasuk Kawamatawong MD, FCCP

Division of Pulmonary and Critical Care Medicine

Department of Medicine

Ramathibodi Hospital Mahidol University

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 2014Global Initiative for Chronic Obstructive Lung Disease. 2013

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

Clinical features distinguished asthma from COPDFor 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

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

Spirometry for COPD Diagnosis and Classification of Severity

5

4

3

2

1

1 2 3 4 5 6

Lit

ers 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

Dutch hypothesis

Common cause ?

Common mechanisms

Asthma COPD

British hypothesis

Different causes

Different mechanisms

Asthma COPD

COLD or CNSLD

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

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

EnvironmentETS & 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-modelingMucus production

Small airway diseaseEmphysema



Case HN 4047696

• ผปวยชายไทย อาย 64 ป อาชพ ท าธรกจสวนตว • มาดวยอาการไอ มเสมหะในปอด 2 ป เหนอยมากขน มาได 1 ป • 30 ป กอนไดรบการวนจฉยโรคหด จากแพทย ทโรงพยาบาลอน เคยท าการ

ตรวจสารกอภมแพทางผวหนง พบวาแพไรฝน • ไดรบการรกษา แตไมสม าเสมอ มอาการเหนอยเปนครงคราว ใชยาขยาย

หลอดลม ชนดรบประทาน และพนแลวอาการดขน • มประวตสบบหรกนกรอง 10 pack years เลกสบบหรไป 20 ป• มประวตมารดา เปนโรคหด • ผปวยมอาการคดจมกน ามกไหล เปนบางครงเวลาสมผสกบฝนละออง• ตรวจรางกาย พบวาม nasal mucosal swelling both noses

• AP chest diameter, expiratory wheeze both lungs

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

Chest film PA and lateral HN 4047696

Paranasal sinus film HN 4047696

การทดสอบสมรรถภาพปอดสไปโรเมตรย (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

การทดสอบทางหองปฏบตการ

• 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)

ทานจะใหการวนจฉยวาผปวยเปนโรคอะไร เพราะเหตผล • 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

High resolution computed tomography of chest

High resolution computed tomography of chest

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 controlRisk factor for asthma exacerbation

Indicator of spirometryseverity

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

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 CTscan

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

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

Airways inflammation and asthma severity

Djukanović Ratko. et al Am J Respir Crit Care Med 2000

Sputum ECP Sputum Eo count

74 Asthmatics 22 non-atopic control

Eosi

no

ph

ils (

10

3/g

)

10000

1000

100

10

1

4000

1000

100

10

1

ECP

(n

g/m

l)

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

Airways Inflammation and level of treatments

Sputum NeutrophilsSputum Eosinophils

Djukanović Ratko. et al Am J Respir Crit Care Med 2000

Eosi

no

ph

ils (

10

3/g

)

20000

10000

1000

100

10

1

100000

10000

1000

100

10

Control LowICS Mild

mod

HighICS

severe

Neu

tro

ph

ils (

10

3/g

)

OCS- OCS+

severeControl Low

ICS Mild to mod

HighICS

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

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

Partial reversible obstructive COPD Increased FeNO and Sputum Eosinophilia

63.8 2.7 9 26.64.1 pack-y

KCO 62.2 %

66.7 ±3.1 923.6 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

Spu

tum

cel

l co

un

ts (

%)

Neutrophils Eosinophils

Control COPD Not Rev

COPD Rev

Control COPD Not Rev

COPD Rev

100

0COPD

Rev

COPD Not Rev

Control

Exh

aled

NO

(p

pb

)

61.7.4.5

FEV

1in

crea

se a

fter

sal

bu

tam

ol (

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 albuterolis associated with increased exhaled NO and sputum eosinophilia


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 %


FeNOSputum Eo count

25%

15

10

5

0

Spu

tum

eo

sin

op

hils

%

Exh

aled

NO

(p

pb

)

60

40

20

0

COPD Asthma COPD Asthma

Bronchial biopsy EG2+ stain and R-BM Asthma with fixed obstruction COPD


EG2+ stain

H&E stain

Different phenotypes of fixed chronic airway obstruction from induced sputum

Maria Laura Bartoli et al Respiration 2009

Asthma COPDFEV1 46.2 ± 6.9 % vs . 50.9 ± 12.6 % Age 58.0 ± 10.5 y vs. 71.9 ± 5.7 y

N =45

Asthma COPDFEV1 46.2 ± 6.9 % vs . 50.9 ± 12.6 % Age 58.0 ± 10.5 y vs. 71.9 ± 5.7 y

Eosi

no

ph

ils (

%)

Asthma CB Emphysema

ECP

(p

g/m

l)

Asthma CB Emphysema

Neu

tro

ph

ils (

%)

Asthma CB Emphysema

NE

(p

g/m

l)

Asthma CB Emphysema

Neutrophilic asthma vs. COPD HRCT detected bronchial wall thickness (BWT)

Neurtopilic asthma65 (10) y, atopy (90%)Smoke 20 packs FEV1 62.1% KCO 97.0%

COPD68 (7) y atopy (47%)Smoke 67.5 packsFEV1 57.6%KCO 56.5%

Smoker control62 (12) y atopy (47%)Smoke 38 packs FEV1 101 %KCO 73.1%

All participants n =35

NeutrophilicAsthma

COPD SmokerControl

Peter G. Gibson et al. Respir Med 2009

Bro

nch

ial w

all t

hic

knes

s sc

ore

10

8

6

4

2

0Bronchial wall thickness score

FEV

1p

red

icte

d (

%)

100 %

80

60

40

20

0

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

The reproducibility of reversibility defined according

to ATS- ERS criteria

Total % notreversible

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

Physiologic differences between asthma and COPD

Physiology Asthma COPD

Elastic recoil Normal Decreased

Diffusion capacity (DLCO)

Normal or increased Decreased

Lung volume Normal Hyperinflation

Bronchodilatorresponse

Flow-dominant (FEV1

response) Volume dependent

(FVC response)

Sciurba FC. Chest 2004; 126: 117-124

Normal Volume dependentobstruction

Obstruction withreversibility

Flow and volume responses reversibility testing in mild-severe COPD

Tjard Schermer et al Resp Med 2007

N =2210

FVC

Ch

ange

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)

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

Mea

n F

VC

res

po

nse

Mea

n F

EV1

res

po

nse

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

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%)

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

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 meanRank sum test for nonparametric

Lueprasitsakul K et al Abstract Eur Resp J 2014

ทานจะใหการรกษาผปวยโดยการใชยาอยางไร

• 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 cessationVaccination

41

GOLD multidimensional assessment of COPDR

isk

(GO

LD C

lass

ific

atio

n o

f A

irfl

ow

Lim

itat

ion

)

Ris

k (E

xace

rbat

ion

his

tory

)

> 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 0-1CAT < 10CCQ <1

mMRC > 2CAT > 10CCQ ≥1

FEV

1≥

50

%

FEV

1<5

0%

CAT score =3+3+2+2+2+2+2+3 =19MMRC= 1

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

Red

uce

In

crea

se

Management approach based on control GINA

Pharmacologic treatment GOLD 2013

Patient Recommended first choices Alternative choices Other possible choices

A SAMA prnor

SABA prn

LAMA orLABA or

SABA and SAMA

Theophylline

B LAMAor

LABA

LAMA and LABA SABA and/or SAMA orSAMA or

TheophyllineC ICS + LABA

orLAMA

LAMA and LABALAMA and PDE4-inh.LABA and PDE4 inh.

SABA and/or SAMA orSAMA or

TheophyllineD ICS + LABA

and/ orLAMA

ICS + LABA and LAMA orICS+LABA and PDE4-inh. or

LAMA and LABA orLAMA and PDE4-inh.

Carbocysteine orSABA and/or SAMA or

SAMA orTheophylline

GOLD guideline 2013

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

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

ICS/LABA vs. LABA Outcome: PneumoniaAnalysis broken down by ICS/LABA type

Nannini et al. Cochrane Database Syst Rev 2012; 9: CD006829

Study/ subgroupCombination

n/NLABAn/N

Odds ratioM-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 estimableKardos 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.

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

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

medications1 (4.0%) 55 (65.5%) <0.05*

Panumatrassamee C at al. Respirology 2014

การทดสอบสมรรถภาพปอดสไปโรเมตรย (13/10/2014)

PFT parameter

Predicted value



% 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

หลงรกษาดวย ICS-LABA-LAMA 6 เดอน (13/10/2014)

PFT parameter

Predicted value



% 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



% 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

การทดสอบสมรรถภาพปอดสไปโรเมตรย 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

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

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

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

Diagnostic Criteria of the ACOS That Had Been Agreed Upon

% agreement in order to beconsider 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 mlover 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

โรคหด Asthma Syndrome

โรคปอดอดกนเรอรง COPD Syndrome

โรคหดผสมโรคปอดอดกนเรอรงAsthma COPD Overlap Syndrome (ACOS)

AtopyCigarette smoking Biomass exposure

Smooth Muscle dysfunction Small Airway inflammation and repair

ปจจยกระตน Triggers

BronchoconstrictionAbnormal 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 และการก าเรบฉบพลน Symptoms and Exacerbation

ACOS prevalence in obstructive airway diseases treated in different sites

Amir A. Zeki et al. J of Allergy 2011

Asthma COPD Emphysema

OverlapSyndrome

Other

43.1

23.3 19.913.7

50%

40%

30%

20%

10%

0

NS

**

*


OverlapSyndrome

Other

34.243.4

15.8

6.6

50%

40%

30%

20%

10%

0

**

*

Types of obstructive airway diseases in general pulmonary clinic


OverlapSyndrome

Other

52.9

23.421.4

50%

40%

30%

20%

10%

0

**

*

1.4

**

Types of obstructive airway diseases in severe asthma clinic


Age and gender distribution of ACOS


% 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

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

% s

ub

ject

s

50%

40%

30%

20%

10%

0

% s

ub

ject

s

50%

40%

30%

20%

10%

0

COPD and asthma42.7

COPD and asthma32.8%

COPD 17.6%

COPD 18%

Impact of ACOS syndrome

A C

OS

61

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*

Spu

tum

eo

sin

op

hils

%

∆ 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

กลมอาการ Asthma

(severe)

Asthma and COPD

Overlap Syndrome

COPD

ลกษณะประชากร อาย > 40 ป อาย > 40 ป (50-65 ป) อาย > 65 ป

ผหญง > ผชาย Varied ผชาย > ผหญง 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

โรครวม (co-morbidities)

Rhino-sinusitis

Obesity

GERD

Rhinosinusitis

GERD

GERD

CAD

Metabolic syndrome

ปญหาทส าคญ Frequent

exacerbation

Very frequent

exacerbation> COPD

Exacerbation and exercise

intolerance

ลกษณณะทางพยาธ

สรรวทยา

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

Positions for COPD treatmentPhenotypic approach

C DB

AExac

erb

atio

n f

req

uen

cy

0-1

/yea

r>2

/yea

r

Emphysematousphenotype

Asthma/COPD Phenotype

Chronic bronchiticphenotype

Treatment of COPD by Clinical Phenotypes

C D

A BA

irfl

ow

lim

itat

ion

by

GO

LD s

tage

4

3

2

1

Exacerbatio

n freq

uen

cy

>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

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 patientii) 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


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

Step 1 Diagnosis Chronic Airway Disease

Do symptoms suggest chronic airway disease?

Yes


Diagnosis Asthma Some feature of asthma

Feature of both

Some feature ofCOPD

COPD

Confidence in diagnosis

Asthma Possible asthma

Could be ACOS Possible COPD COPD

Step 3Perform spirometry

Post BD FEV1/FVC <0.7 Marked reversible airflow limitation (pre post DB)or other proof of variable airflow limitation

Step 4 Initial treatment

Asthma drugno LABA mono-Rx

Asthma drugsno LABA mono-Rx

ICS and LABA +/-LAMA

COPD drugs COPD drugs

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.

Risk factors

Gender Age BMI Infectious (Rhinovirus, influenza, mycoplasma, chlamydia)AHR Smoking Allergies Acute exacerbation Pollution/environmental toxin

In utero orEarly 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 inhibitorMast cell stabilizer TheophyllineOmalizumabBronchial thermoplasty

Know treatments Smoking cessation Pulmonary rehabilitation ICS, LABA, LAMA CS, TheophyllineOxygen therapyPulmonary rehabilitationLung volume reduction surgery (RVRS) Endoscopic LVRS

Obstructive airway diseases in practicePhenotypic approach: No one size fit all

C DB

AExac

erb

atio

n f

req

ue

ncy

0-1

/ye

ar>2

/ye

ar

Emphysematousphenotype

Asthma/COPD (ACOS) Phenotype

Chronic bronchiticphenotype

Treatment of COPD by Clinical and Imaging Phenotypes

M. Miravitlles et al. Eur Respir J. 2013; 41(6)1252-6

Science

Asthma and copd overlap syndrome (acos) tst edited ramathibodi