Controversial in Asthma (20-22 Mar 2016) Final

Controversial Issues
in Asthma 2016
Controversial Issues
in Asthma 2016

1. .. 2559 .. 1
2. Asthma: Year in Review 2016 . 43

3. Omalizumab (Anti-IgE in Severe Allergic Asthma)..... 51

4. ... 67
(Diagnosis and treatments of Asthma-COPD Overlap Syndrome: ACOS)
/
5. 87
(Preschool wheezing: which one is asthma?)

6. Small airway diseases in asthma: Is it really that small? ... 99

7. ... 117
(Allergen-specific immunotherapy for childhood asthma)
/
8. . 129
(Rhinosinusitis: Is it important in asthma management?)

2559

9. .. 2558 .151

10. 179
(Acute asthma management: Whats new in 2015-16)

11. ..191
(Asthma prevention in children: is it possible?)

12. Chronic Eosinophilic Pneumonia .. 201

13. difficult severe asthma 215

2559
Controversial Issues in Asthma 2016

.. 2559

(Strength of Recommendation)
++
(cost effective)
+

+/-

-

- -

(Quality of Evidence)
1
1.1 (systematic review) -
(randomize-controlled clinical trials)
1.2 -
1 (a well-designed
randomize -controlled clinical trial)
2
2.1 (non-randomized controlled
clinical trials)
2559
2.2 (well-designed, non- randomized

controlled clinical trial)
2.3 (cohort)
(case control analytic studies)
/
2.4 (multiple time series)

.. 2480

3
3.1 (descriptive studies)
3.2
(fair-designed, controlled clinical trial)
4
4.1 (consensus)

4.2 2

(anecdotal report)

2559
(heterogeneus disease)

(variable expiratory airflow
limitation)
7 2 ( +)
(variable symptoms) variable expiratory
airflow limitation (airflow limitation)

(airway hyper-responsiveness)

airflow limitation
(exacerbation)
1

1)
2) variable expiratory airflow limitation
(spirometry)

(controller)
peak expiratory
flow (PEF) variability 1 ( +,
4)
2559

(eczema)
asthma phenotype

/
COPD, upper airway obstruction, , tracheobronchomalacia
crackles
inferior turbinate nasal polyp
(airflow limitation)

1)
2) (reversibility) /
(variable airflow limitation)
FEV1/FVC 0.75-0.8 60
2559
FEV1 200 ml 12
15 /
4 3 (variable airflow obstruction)
(alternative options)
1. peak expiratory flow (PEF)
1.1 PEF 60 L/min 20

PEF (
+, 4)
1.2 PEF PEF 1-2

PEF 2 PEF variable
5-9 PEF variable 9-20
PEF variability 20 10 PEFR
variability PEF variability (
++, 1)
1.3 PEF 20 4
( +, 1)
2. (airway hyper-responsiveness, AHR)

methacholine
FEV1 20 baseline (PC20)
PC20 1 mg/ml (severe AHR) PC20 4 mg/ml
PC20 16 mg/ml
(sensitivity) (specificity)
PC20 8 mg/ml 4
2559

( +, 4)
1)
2)
3)
4)

( 1) ( +, 4)
1

Dyspnea on exertion
Hemoptysis
Localized wheezing
Structural airway
obstruction

Persistence of central wheezing/
stridor
Upper airway obstruction
Wheezing aggravated by forced
Posterior wall of airway
COPD (stable)
Bronchiectasis
Lung cancer
TB
Bronchiectasis
Lung cancer
Bronchostenosis endobronchial TB
Tracheal stenosis
Tracheal tumor
Bilateral vocal cord paralysis
Lung cancer with tracheal invasion
Esophageal cancer invaded trachea
TB larynx, TB involved trachea
Tracheobronchomalacia
2559
expiration or cough
collapse
Sudden onset of wheezing that
spontaneously resolved abruptly
Hoarseness of voice, lump in throat
Wheezing with clubbing of finger
Vocal cord dysfunction
Bronchiectasis
Lung cancer
Lung abscess
Lung cancer
Cervical lymphadenopathy

Abnormal chest X-ray that explain
wheezing, cough, dyspnea
Spirometry showed irreversible
airway obstruction
Hypoxemia without hypercarbia
Pulmonary congestion
COPD
Bronchiectasis
Chronic asthma with remodelling
Heart failure (cardiac wheezing)
Pneumonia
Atelectasis
Pulmonary embolism

( +, 4)

(mild asthma)

(moderate asthma)

(severe asthma)
PEF or FEV1 / PEF variability
< 1 < 2
> 80% / < 20%
> 1 > 2

> 1
> 80% / < 20-30%

< 60%-80% / > 30%
asthma
symptom control
2559
(Assessment of asthma)

(Assessing asthma control)
(FEV1)

(categorical symptoms control) (composite score
numerical symptom control) asthma control test (ACT)5 asthma control questionnaire
(ACQ)6
(symptom assessment) 2

4 ( +, 4)
4
2
(Risk factors for poor asthma outcome)

(asthma controller medication)
(Risk factors for exacerbation)
(Risk factors for developing fixed airflow obstruction)
(Risk factors of medication side effect)1
2559
(Poor asthma outcome)

(Risk factors of exacerbation)

(Risk factors for developing fixed
airway obstruction)

(Risk factors of medication side
effects)

> 200 /

FEV1

eosinophils
:

P450 inhibitor
:

(<60% predicted)

eosinophils

(inhaled corticosteroids, ICS)

2559
10
(asthma
controlled)
(asthma control)
(current control)

(prevent future risks)

(remodeling)
1

(prevent future risks)

(LABA)
theophylline
LABA (ICS/LABA)
ICS/LABA formoterol LABA
(Maintenance and Reliever
Therapy)7 ( ++, 1) 1
2559
11

(Medications and strategies for symptom control and risk reduction)1
(Asthma medications) (stepwise
approach) (asthma control)
3 1
1) (Asthma controller medications)
(fixed airflow obstruction)
2) (Symptoms rescuer reliever medication) (as-needed)
(exercise induced
bronchospasm, EIB)
3) (Add on therapies) (severe asthma)

(ICS/LABA)
(Initial controller)
2

2
2 1
( 2)
1 / 1
( ++,
3)

(asthma severity)
( )
3-6
2559
12
Treatment steps
Decrease
Step 1
Step 2
Step 3
Increase
Step 4
Step 5
Asthma education, environmental control, influenza vaccine and pulmonary rehabilitation

Low dose
steroid
High Risk
exacerbation
Low dose
steroid

High Risk
exacerbation
Select one
Low-dose
inhaled ICS
Leukotriene
modifier
As needed rapid-acting 2-agonist

Select one
Add one or more
Low-dose ICS plus Medium-or high-dose
long-acting
ICS plus long-acting
2 -agonist
Medium-or- highdose ICS
Low-dose ICS plus
leukotriene modifier
Low dose ICS plus
sustained release
theophylline
2-agonist
Leukotriene modifier
Add one or both

Oral
glucocorticosteroid
(lowest dose)
Anti - IgE
Sustained release
theophyline
Tiotropium bromide
1 (asthma treatment level)

( RABA = rapid acting 2 agonist, ICS = inhaled corticosteroid, ICS/LABA = inhaled

corticosteroid plus long acting 2 agonist, LTRA = leukotriene receptor antagonist, OCS = oral
corticosteroid)
(Preferred options) (alternatives others)

2559
13
1
(As needed inhaled rapid acting 2-agonist)
ipratropium bromide rapid acting 2-agonist
theophylline

( ++, 1)8, 9 2
(risk factors)
(controller medications)10, 11 (low dose ICS)
( ++, 1)
2 (low dose ICS)
(
+++, 1)10, 12

( +++,
1)13, 14

4 ( 3) theophylline

15, 16 ( 1)
3
(ICS/LABA) 17,9,18
formoterol (ICS/formoterol)
budesonide/formoterol beclomethasone/formoterol)
(maintenance and reliever therapy)7, 19-23
ICS/LABA combination
2559
14
24 11, 25, 26
27
theophylline 28
(ICS/LABA)29, 30 ( +++,
1)
4 2

(medium dose ICS/LABA)17, 24
4
1
formoterol

24 (
+++, 1)

17 ( +++, 2)

3-6 25

theophylline 31 ( ++, 2)
tiotropium 5 10 g ICS/LABA
32, 33
2559
15
theophylline

28, 34 ( ++, 2)
5 ()
(high
dose ICS/LABA) (Anti-IgE treatment
omalizumab) ( 1) (Add-on low dose
oral corticosteroid) ( 3) bronchial thermoplasty
( 2)
(monoclonal anti-IgE omalizumab)
allergic asthma
(aeroallergen) specific IgE (aeroallergen)
omalizumab 35, 36 omalizumab
( 2)

(aeroallergen) total
IgE 30-1500 IU/ml37 16
1 38-41 omalizumab
35, 42 ( +++,
1)
prednisolone 7.5 mg
43, 44( +++,
3) bronchial thermoplasty

45, 46 eosinophils
(sputum eosinophil guided treatment) 47, 48
( +, 1)
(comorbidities),
, tracheobronchomalacia
2559
16
(Controller medications)
1. (ICS)
beclomethasone, budesonide, fluticasone

prednisolone
hydrocortisone,
dexamethasone, methylprednisolone
fluticasonse-salmeterol, budesonide-formoterol,
mometasone-formoterol, beclomethasone-formoterol
theophylline doxophylline
omalizumab
tiotropium handihaler tiotropium respimat

salbutamol, terbutaline, procaterol fenoterol
aminophylline
salbutamol, terbutaline procaterol
salbutamol-ipatropium bromide fenoterol-ipatropium
bromide
2.
3. xanthine
4. Anti-IgE
5. Long acting anticholinergic
(Reliever medications)
1.
2.

(Stepping down asthma treatment when achieved control)

(nocturnal symptoms)
FEV1 2 (airway hyperresponsiveness) 49
(step down therapy) 312

2559
17

( ++, 1)50

( +,
4)
1.
2.
3. (written action plan) 5
4.
5.

checklist

1)
2559
18
2)

3)

4)

1)
2)
3)
4)
5)
6)
7)

1) peak expiratory
flow rate
2) (asthma action plan)
()

2559
19
(
)

1) (peak inspiratory flow rate) 30-60 L/min DPI
accuhaler (30 L/min) turbuhaler (60 L/min)51 ( ++,
2)
2) pMDI
pMDI spacer
3) DPI turbuhaler, accuhaler

4)
5)

Guideline Implementation

3
12
(Easy Asthma Clinic)13 .. 2547

2559
20
Easy Asthma Clinic

online

250,000 (
http://eac2.easyasthma.com/)
Easy Asthma Clinic
1. ()
(asthma control questionnaires) ()
(Peak Expiratory Flow Rate, PEFR)
(asthma control questionnaires)
4
1.1 4

1.2 4

1.3 4 () ?
1.4 2

2.

(
80 )
(500-1000
g) 3
LABA, theophylline
2559
21
3.

4. http://eac2.easyasthma.com/

expiratory airflow
peak expiratory flow rate (PEFR) forced expiratory volume in 1 second (FEV1)

(relapse)
(admission) (mortality)
1.
( 2) ( +,
4)
air
hunger
2
(mild to moderate)
(severe)
100-120 /
>120 /
< 30 /
>30 /
oxygen saturation (room air)
90-95 %
< 90% or cyanosis
PEF
PEF > 50% predicted or best
PEF < 50% predicted or best
2559
22
1

2. (SpO2)
93 SpO2 SpO2 9352-54
( ++, 2)
3. (inhaled rapid-acting 2
agonist, RABA) RABA
15-20
RABA
3.1 RABA salbutamol 2.5-5 . nebulization salbutamol 400-1,000 .
(4-10 puffs) pMDI spacer 15-20
20 55
3 ( ++, 1)
3.2 RABA 3 (severe)
RABA short-acting anticholinergic

RABA ( ++,
1)
4. systemic corticosteroids systemic corticosteroid
( 1)
RABA
dexamethasone 4-5 . hydrocortisone 100 . 6-8
prednisolone 30-50 . (0.5-1 mg/kg/d)
systemic corticosteroid prednisolone
5-7 56-58 ( ++, 1)
2559
23
systemic steroid
(relapse) 59, 60
5.
(SpO2)
/ SpO2
RABA

peak expiratory flow rate (PEFR)61-63
%predicted ( %personal best)
RABA 15-20

PEFR ( ++, 2)
6.

magnesium sulfate ( )64, 65
( +, 1)
intravenous aminophylline noninvasive ventilation (NIV)
66 (
++, 1) NIV central airway
collapse invasive ventilation
2559
24

(Asthma in pregnancy)

67
(exacerbation) 2
exacerbation

68

, 2-agonist, montelukast
theophylline

94
regional anesthesia general anesthesia
69 ( +, 3)
(Asthma and obesity)

functional residual capacity functional reserved volume
airway obstruction (adipose tissue) (proinflammatory cytokines) oxidative stress
2559
25
systemic inflammation

Aspirin-exacerbated respiratory disease (AERD)

30 70

(anosmia) nasal polyposis hypersensitivity
aspirin (ASA) 1-5 71
aspirin COX-2 inhibitor
AERD
montelukast AERD 72,
73
( ++, 1)
ASA desensitization
74 ( ++,
3) ASA desensitization
75
(Asthma and surgery)

76 (
++, 3)
77 78
FEV1 80
79

79
2 76 ( ++, 3)
prednisolone 1 ././ 40
2559
26
. 5 80 ( ++,
3) 5 79

79 ( ++,
3) salbutamol 81
methylprednisolone 125 . 79
epinephrine 0.5-2 ./
magnesium sulphate 79 ( ++, 3)

2 6 hydrocortisone
2 ././ 100 . 8
adrenal crisis82, 83 ( ++, 2)
(Asthma-COPD overlap syndrome or

ACOS)

AsthmaCOPD overlap syndrome ACOS 15-5084
ACOS syndrome
ACOS
ACOS syndrome

(airway or systemic eosinophilia)
85
ACOS

(ICS/LABA) / long-acting anticholinergic

1, 85
2559
27
1
PEFR variability Peak flow variability

1) PEFR 7-14
pre-bronchodilator PEFR 3
PEFR PEF
PEF 2 986, 87 GINA
PFER variability > 10 > 13
2 1 asthma persistent asthma
2088
PEF variability = average [PEFR highest PEFR lowest]
Mean daily PEF
PEFR (L/min)
p.m
p.m.
600
p.m
500
p.m
p.m.
p.m.
p.m
400
300
a.m.
a.m
a.m.
a.m.
a.m.
a.m.
a.m.
200
100
Time
(days)
D1
D2
D3
D4
D5
2559
D6
D7
28
2
anti-IgE omalizumab
Severe asthma?
Patient age 6 years ?
Controlled with ICS +LABA ?
Multiple documented severe exacerbations ?
Frequent daytime and nocturnal symptoms?
FEV <80% predicted?
Skin prick test positive for aeroallergen?
Serum allergen specific IgE positive?
Yes
20-150 Kg serum total IgE 30-1500 IU/ml?

Consider treating with omalizumab
2559
Patient not suitable for omalizumab
29
3
Asthma Control Questionnaire (ACQ) Asthma Control test
(ACT)
Asthma Control Questionnaire (ACQ)
pre-bronchodilator FEV1 ACQ-5 ACQ-6
ACQ-6
6 0.75
1.5 Asthma Control test 5
25 20
(ACQ-6)
6 1

1.

3
2.

0
3
2559
30
3.

3
4.

0
3
5.
0
3
6. (
) ( )
0
4 9-12
1 1-2
5 13-16
2 3-4
6 16
3 5-8
(Asthma Control Test, ACT) 5
4 25 19

2559
31
(ACT Score)
5

4

1-2
1
4

1
2
3-6
4
(
)
4
3
2-3
1-2
4

4
3

1-2
2-3

4
5

2559
32
4
(Non-pharmacological Therapies)

1 ( ++)
1 Non-pharmacological therapies
&

3 1
1. : 3 , ,

2. :

3. :

2
Exercise training
Exercise training (Tai Chi Qigong)

exercise training

3-5 ( maximum
exercise capacity,VO2max) (exercise
endurance) 3-4 (FVC, IC) 4 6
4,7 (health-care utilities)
oral steroid
8-9
2559
++IV
++II
33
exercise training 5-7

20-30 6-8

(Breathing exercise) 5
++II
(Breathing exercise) , ,
, ,

10-11

(Breathing exercise)
++ IV
adult-onset asthma

12
++III
,

13
-III
NSAIDs beta-blockers
- 8
14-15
10 16

++II
influenza vaccine 1 moderate

severe17 pneumococcal vaccine
2559
++II
+ IV
34
6
18

2559
+ IV
35
5
(asthma action plan)
asthma care

(Action Plan)
-
-
(2 agonist) 15
3 2 3
-
B2 agonist
15
* (Action Plan)

2559
36
2559
37

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38. Molimard M, Mala L, Bourdeix I, Le Gros V. Observational study in severe asthmatic patients after discontinuation of
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42. M. Beeh K. Which patients should be treated with anti-IgE? EUROPEAN RESPIRATORY REVIEW. 2007;16(104):85-7.
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51. van der Palen J. Peak inspiratory flow through diskus and turbuhaler, measured by means of a peak inspiratory flow meter (InCheck DIAL). Respir Med. 2003;97(3):285-9.
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70. Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory
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montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med.
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74. Pleskow WW, Stevenson DD, Mathison DA, Simon RA, Schatz M, Zeiger RS. Aspirin desensitization in aspirin-sensitive
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75. Lee RU, Stevenson DD. Aspirin-exacerbated respiratory disease: evaluation and management. Allergy Asthma Immunol Res.
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markedly decrease the incidence of bronchospasm after tracheal intubation. Anesthesiology. 2004;100(5):1052-7.
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Elderly. J Allergy (Cairo). 2011;2011:861926.
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habits in a random population sample aged 20-70 yrs. Eur Respir J. 1994;7(10):1814-20.
87. Gannon PF, Newton DT, Pantin CF, Burge PS. Effect of the number of peak expiratory flow readings per day on the estimation of
diurnal variation. Thorax. 1998;53(9):790-2.
88. Hetzel MR, Clark TJ. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax.
1980;35(10):732-8.
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43
Asthma: Year in Review 2016

1. Calcium channel blocker airway remodeling severe asthma
Bronchial smooth muscle (BSM) remodeling bronchial smooth muscle
mass severe asthma
BSM cells
BSM cells extracellular calcium influx in vitro
gallopamil CCB Ca++ mitochondrial biogenesis
mitochondrial mass BSM1
double-blinded, randomized-controlled (RCT)
gallopamil remodeling 2 sever e asthma
American Thoracic Society3
10 pack-year 3
6 2 gallopamil 16
15 1 3
remodeling (M0) 12 (M12)
primary endpoint BSM area
BSM surface
secondary endpoint normalized BSM thickness, BSM thickness ( % BSM area
),
2
2 12 BSM area
M0 M12
gallopamil gallopamil BSM area
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normalized BSM thickness gallopamil

1
3 gallopamil

calcium-channel blocker
airway remodeling severe asthma
gallopamil normalized BSM
thickness
remodeling 3
4
CCB remodeling
remodeling severe asthma

2. Nonsteroidal Glucocorticoid Receptor Agonist: Allergen-induced late
asthmatic responses
(Glucocorticosteroids, GCSs)
GCSs intracellular glucocorticoid receptor (GR)
hypothalamic-pituitary-adrenal
axis (HPA axis), AZD5423
nonsteroidal, potent selective modulator GR receptor GCSs
GCSs systemic 5
inhaled allergen allergic asthma
AZD5423 6 mild, atopic, stable asthma
18-60 FEV1 70 27
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RCT cross-over 16-21

AZD5423 2 budesonide primary outcome
FEV1 late asthmatic response (LARs) secondary outcome
FEV1 early asthmatic response (EARs), airway
hyperresponsiveness (screening period)
airway hyperresponsiveness (AHR), skin prick test,
(treatment period) 7
budesonide, AZD5423 300 , AZD5423 75
2
primary outcome FEV1 LARs
AZD5423 300 -8.4%, AZD5423 75 -8.7%
(P<0.05) budesonide -12.1% PC20
5
PC20 7
5 AZD5423 75
(P=0.012) AHR
1
7 AZD5423 300 PC20
(P=0.016)
6 7 AZD5423 2
budesonide AZD5423
300
HPA axis
AZD5423 nonsteroidal GR agonist
mild allergic asthma LARs EARs
GR agonist GCSs
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budesonide
3. adult-onset incident asthma

(adult-onset asthma) oxidative stress
antioxidant 2 nonenzymatic dietary antioxidant
tocopherols, carotenes, xanthines, lycopene enzymatic antioxidant
superoxide dismutase antioxidant

antioxidant
enzymatic nonenzymatic (incidence)
7
Shanghai Womens Asthma and Allergy Study 65,372
8 2
2 8
2

methacholine challenge test nested study
(N = 150) (N = 294) oxidative stress antioxidant

antioxidant alpha-tocopherol
2
48 (OR =
0.52; 95% CI, 0.32-0.84; P = 0.007) antioxidant beta-carotene, alpha-carotene,
lycopene antioxidant enzyme
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activity platelet-activating factor acetylhydrolase (PAF-AH)

2 OR=0.63; 95% CI, 0.420.93; P=0.02
10 nmol/ml/min 6-16 superoxide dismutase (SOD)

SOD
antioxidant non-enzymatic
enzymatic antioxidant PAF-AH
PAF-AH PAF PAF-like phospholipids
mucus 8

antioxidant

enzymatic non-enzymatic antioxidant
antioxidant
antioxidant (primary prevention)
(secondary prevention)
4. Tiotropium : Systematic review Meta-analysis
..2015 tiotropium metaanalysis tiotropium
6 9
Rodrigo 10 systematic review

tiotropium
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12
ICS ICS long-acting beta2 agonist (LABA) randomizedcontrolled (RCT) 4 tiotropium
1 primary outcome
secondary outcome rescuer, asthma symptom-free days/week, (MiniAsthma Quality of Life Questionnaire [AQLQ] total score), asthma control (Asthma Control
Questionnaire 7 (ACQ-7) total score), ACQ-7 responder rate (
ACQ-7 score 0.5 ),
RCT 13 4,966
3 1 tiotropium ICS mild-moderate asthma 2 tiotropium
ICS LABA+ICS moderate asthma 3 tiotropium
LABA+ICS LABA+ICS severe asthma
4-52
tiotropium soft mist inhaler (respimat) 5 2
18
1 (tiotropium ICS) peak expiratory flow (PEF)
( 22-24 L/min, P<.00001) peak trough FEV1
(peak FEV1 150 mL; P<.00001) (trough FEV 1 140 mL; P<.00001)
ICS AQLQ ACQ-7 total scores minimal clinically
important difference (MCID) number
needed to treat = 36 asthma symptom-free days ICS
2 (tiotropium + ICS LABA+ICS)
FEV1 peak trough, PEF , asthma symptom-free day, ACQ-7,
tiotropium LABA PEF LABA tiotropium
rescuer, AQLQ total score MCID
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3 (tiotropium LABA+ICS)
NNTB = 17 ACQ-7 MCID NNT = 8

systematic review tiotropium stable asthma
5,000
40 12

tiotropium salmeterol moderate
ICS ICS+LABA tiotropium
LABA ICS mild-moderate asthma severe
asthma LABA+ICS tiotropium 5
soft mist inhaler (respimat) tiotropium

1. Trian T, Benard G, Begueret H, Rossignol R, Girodet PO, Ghosh D, et al. Bronchial smooth muscle
remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma. J Exp Med.
2007;204(13):3173-81.
2. Girodet PO, Dournes G, Thumerel M, Begueret H, Dos Santos P, Ozier A, et al. Calcium channel blocker
reduces airway remodeling in severe asthma. A proof-of-concept study. Am J Respir Crit Care Med.
2015;191(8):876-83.
3. Proceedings of the ATS Workshop on Refractory Asthma. Am J Respir Crit Care Med. 2000;162(6):2341-51.
4. Sumino K, Sheshadri A, Castro M. Calcium Channel Blocker Reduces Airway RemodelingOr Does It? Am J
5. Kallstrom L, Brattsand R, Lovgren U, Svensjo E, Roempke K. A rat model for testing anti-inflammatory action
in lung and the effect of glucocorticosteroids (GCS) in this model. Agents Actions. 1986;17(3-4):355-7.
6. Gauvreau GM, Boulet LP, Leigh R, Cockcroft DW, Killian KJ, Davis BE, et al. A nonsteroidal glucocorticoid
receptor agonist inhibits allergen-induced late asthmatic responses. Am J Respir Crit Care Med.
2015;191(2):161-7.
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7. Larkin EK, Gao Y-T, Gebretsadik T, Hartman TJ, Wu P, Wen W, et al. New Risk Factors for Adult-Onset
Incident Asthma. A Nested CaseControl Study of Host Antioxidant Defense. Am J Respir Crit Care Med.
2014;191(1):45-53.
8. Cuss FM, Dixon CM, Barnes PJ. Effects of inhaled platelet activating factor on pulmonary function and
bronchial responsiveness in man. Lancet. 1986;2(8500):189-92.
9. Tian JW, Chen JW, Chen R, Chen X. Tiotropium versus placebo for inadequately controlled asthma: a metaanalysis. Respir Care. 2014;59(5):654-66.
10. Rodrigo GJ, Castro-Rodriguez JA. What is the role of tiotropium in asthma?: a systematic review with metaanalysis. Chest. 2015;147(2):388-96.
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Omalizumab
(Anti-IgE in Severe Allergic Asthma)

anti-IgE omalizumab severe allergic asthma 10
monoclonal antibody IgE
omalizumab added on therapy
randomized controlled trial real world study
omalizumab omalizumab
Real world study
omalizumab asthma (OXYGEN study)
IgE B cells (plasma cells) T cells IgE
plasma cells Fc RI
(selective) (high affinity) mast cells basophils
degranulation pro-inflammatory mediators
allergic diseases vasodilators, bronchoconstrictors, mucus
secretagogues sensory nerve mediators
recruitment cells eosinophils basophils (cellular infiltration)
1
Omalizumab recombinant DNA-derived humanized monoclonal antibody
anti-IgE antibody humanization murine residue 5%
omalizumab1 high affinity Fc domain IgE IgE
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antigenic site 2 omalizumab 2 3 form trimer (

500 kD) 1 omalizumab 2 antigenic loci (VH VL of IgG)
IgE 2 omalizumab IgE anti-IgE/IgE complex
trimer ( 500 kD) hexamers ( 1000 kD) anti-IgE/IgE
complex (inert) reticuloendothelial system
(RE system)4
omalizumab allergic disease

circulating free IgE
IgE FcRI mast cells

inflammatory mediator cell degranulation eosinophil recruitment
expression FcRI mast cells2
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IgE C3 FcRI ( mast cells

basophils) FcRII (CD23) ( B lymphocytes monocytes) IgE
FcRI cell degranulation release inflammatory mediators allergic
inflammation IgE FcRII (CD23) up-regulation IgE synthesis
B cells3
Omalizumab IgE IgE FcRI
mast cells basophils cell degranulation omalizumab
IgE FcRI expression FcRI mast cells basophils 90%
IgE omalizumab free IgE 90%
mast cells allergen challenge4 allergic inflammation symptoms
asthma allergic disease IgE synthesis IgE
FcRII (CD23) B cells5 omalizumab IgE FcRI
cells (receptor bound IgE) omalizumab cross link mast
cells degranulation2
omalizumab improve clinical outcome added
on uncontrolled asthma ICS ICS LABA pooled
analysis 7 6 anaphylaxis 0.01%
omalizumab EU severe persistent allergic asthma
ICS LABA 6 US FDA moderate to severe
persistent allergic asthma ICS 12 2007
53 omalizumab 6 GINA guideline
2007 2014 omalizumab added on therapy step 5

GINA guideline low dose oral corticosteroid7
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54
omalizumab
omalizumab EU
added on therapy 6 severe persistent allergic asthma
8
omalizumab8
1) atopic asthma allergen skin test serum specific IgE in
vitro reactivity ( radioallergosorbent test [RAST] ) perennial respiratory aeroallergen
2) (FEV1 < 80%)

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55
3)
4) (frequent asthma exacerbation)
5) inhaled corticosteroid long acting beta2 agonist
omalizumab GINA guideline 2007

step 5 added on therapy inhaled corticosteroid long acting beta
agonist 7
omalizumab
(pre-treatment
baseline characteristics) 16 (16-week
therapeutic trial) 8
(dose) omalizumab
2
1) Serum total IgE
(clinical efficacy) serum free IgE

50 ng/ml ( 20.8 IU/ml) IgE 12 ng/ml
IgE 25 ng/ml (10.4 IU/ml) baseline serum total IgE molar
excess omalizumab : IgE ( 7:1 15:1) optimize efficacy antiIgE total serum IgE 9
2)
total body weight ideal body weight volume of distribution
body fat clearance body weight10 omalizumab

(vial) 202.5 mg reconstituting 150 mg
reconstitution 20 4 8
half life IgG (IgG1 isotype) 3-4
300 mg 2 150 mg
bioavailability 62% free IgE 1 10
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56
dose 0.016 mg
omalizumab/kg
body
weight/international unit IgE

dose suppress circulating
IgE 15 IU/ml10, 11 serum IgE omalizumab
commercial assay unbound IgE IgE bound omalizumab
10

omalizumab

serum total IgE omalizumab serum
total IgE
asthma exacerbation
AQLQ
(FEV1) total serum IgE 76 IU/ml 12
serum specific IgE aeroallergen 13

(omalizumab responders) 16
responder 2 6
1) (overall physician assessment)
2) (composite measure of asthma control)
PEFR

(overall physician assessment) 5
(patient report outcome PRO) questionnaire
asthma related quality of life AQLQ 0.5
responder composite score asthma control level Asthma control test score ACT
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57
score 2 responder

responder 6
a) FEV1 200 ml
b) daytime symptoms 1 ( 4-point scales : 0
4 major symptoms)
c) nighttime symptoms 1 ( 4-point scales : 0
4 major symptoms)
d) nocturnal awakening 1 50%
INNOVATE14 study
(clinical significant exacerbation) omalizumab
responder physicians overall assessment AQLQ ACT

responder (composite score)
FEV1 symptoms score
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58
omalizumab
physician overall assessment
subjective 8

objective measurement
key assessment criteria ACT score, mini-AQLQ physician assessment
supportive criteria PEFR, exacerbation, unscheduled healthcare utilization (HCU)
omalizumab15
omalizumab8, 12, 15
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59
omalizumab
asthma chronic disease
omalizumab 52 12-24
rebound effect15
serum free IgE
serum IgE

FcRI mast cells basophils
free IgE
11
skin prick test
wheal flare reaction 16

omalizumab
6 omalizumab 12-14
(12 18 ) 17, 18
omalizumab induce long
term remission 18
targeted therapies biologic agents omalizumab

omalizumab added on therapy ICS-LABA combination Quality
adjusted life years (QALY) model incremental cost exchange ratio
(cost effective) 12
multicenter study
INNOVATE14 omalizumab ICS-LABA

biologic agent rheumatoid arthritis multiple
sclerosis
omalizumab
16
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60

16
(treatment responder)12 continue

omalizumab FEV1
omalizumab

FEV16 free IgE
1 0
omalizumab FEV1 open label
omalizumab FEV1 exacerbation
frequency improvement of airflow limitation exacerbation
exacerbation prone asthma phenotype bronchial luminal narrowing repetitive
exacerbation driven airway inflammation19, 20
omalizumab 16 FEV1 (prebronchodilator FEV1) clinical significant exacerbation
oral corticosteroid
Real world study efficacy omalizumab asthma (OXYGEN study)
omalizumab randomized controlled trials (RCT)
INNOVATE study efficacy
(confounder) real world evidence (RWE) retrospective
observational studies post marketing
effectiveness
(external validity) RCT

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clinical trial
RWE
RWE omalizumab
omalizumab eXpeRience
study multicenter 294 baseline
characteristics
uncontrolled asthma partly controlled asthma 62%
23% multiple asthma medications ICS-LABA, LABA LTRA
allergic rhinitis 42% mean FEV1 62.4% mean serum IgE 316 IU/ml
allergic asthma skin prick test RAST
omalizumab anti-IgE 87.7%21 observational study
(discontinued omalizamab) (responder) 61
22 55.7%
lost asthma control 13 22
The Omalizumab (Xolair) retrospective studY and reGistry in Thai asthmatic patiENts
study OXYGEN study American Academy of Allergy,
Asthma and Immunology (AAAAI) 2014
omalizumab 46 allergic test 97% allergic
rhinitis 84.3% 300 mg serum IgE 493 IU/ml
annual exacerbation rate 5.7 4.1
16 0.8 52 maintenance systemic corticosteroid
28.3% 9.7% 52 89%
1 23
omalizumab
omalizumab
local site injection reaction 2 phase 3
side effect control 3
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anaphylactogenic anaphylactic
anaphylactoid reaction
24
1
polysorbate omalizumab Joint Task Force
2007 American Academy of Allergy, Asthma and Immunology
2003-2005 40,000 anaphylaxis 41 0.09% 2 3
2 3 dose dose 4
30 25
2 3 dose 30
dose epinephrine Omalizumab Joint Task
Force (OJTF) Academy of Allergy, Asthma and Immunology EPR3 report National
Heart Lung and Blood Institute NHBLI25
malignancy omalizumab
malignancy
omalizumab 26
1
omalizumab pre-existing drug induced malignancy
blind independent oncologist causal
relationship 2

B
(US FDA)
27
omalizumab clinically significant asthma exacerbation

improve asthma control ICS-LABA combination

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patient compliance device technique

allergic rhinitis 16
objective measurement

3) Presta LG, Lahr SJ, Shields RL, Porter JP, Gorman CM, Fendly BM, et al. Humanization of an antibody
directed against IgE. J Immunol. 1993;151(5):2623-32.
4) Pelaia G, Gallelli L, Renda T, Romeo P, Busceti MT, Grembiale RD, et al. Update on optimal use of
omalizumab in management of asthma. J Asthma Allergy. 2011;4:49-59.
5) Presta L, Shields R, O'Connell L, Lahr S, Porter J, Gorman C, et al. The binding site on human
immunoglobulin E for its high affinity receptor. J Biol Chem. 1994;269(42):26368-73.
6) Spector S. Omalizumab: efficacy in allergic disease. Panminerva Med. 2004;46(2):141-8.
7) Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. The anti-inflammatory effects of omalizumab
confirm the central role of IgE in allergic inflammation. J Allergy Clin Immunol. 2005;115(3):459-65.
8) Price D. The use of omalizumab in asthma. Prim Care Respir J. 2008;17(2):62-72.
9) GINA. Global strategy for asthma management and prevention 2011. Global Initiative for Asthma 2011 [cited
2012 Jan 2012]; Available from: http://www.ginasthma.org/guidelines-gina-report-global-strategy-forasthma.html.
10) Holgate S, Buhl R, Bousquet J, Smith N, Panahloo Z, Jimenez P. The use of omalizumab in the treatment of
severe allergic asthma: A clinical experience update. Respir Med. 2009;103(8):1098-113.
11) Hochhaus G, Brookman L, Fox H, Johnson C, Matthews J, Ren S, et al. Pharmacodynamics of omalizumab:
implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma. Curr Med
Res Opin. 2003;19(6):491-8.
12) Ledford DK. Omalizumab: overview of pharmacology and efficacy in asthma. Expert Opin Biol Ther.
2009;9(7):933-43.
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13) Slavin RG, Ferioli C, Tannenbaum SJ, Martin C, Blogg M, Lowe PJ. Asthma symptom re-emergence after
omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations. J
Allergy Clin Immunol. 2009;123(1):107-13 e3.
14) Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H, et al. Predicting and evaluating response to
omalizumab in patients with severe allergic asthma. Respir Med. 2007;101(7):1483-92.
15) Wahn U, Martin C, Freeman P, Blogg M, Jimenez P. Relationship between pretreatment specific IgE and the
response to omalizumab therapy. Allergy. 2009;64(12):1780-7.
16) Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on
therapy in patients with severe persistent asthma who are inadequately controlled despite best available
therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60(3):309-16.
17) Holgate S, Buhl R, Bousquet J, Smith N, Panahloo Z, Jimenez P. The use of omalizumab in the treatment of
severe allergic asthma: A clinical experience update. Respiratory medicine. 2009;103(8):1098-113.
18) Corren J, Shapiro G, Reimann J, Deniz Y, Wong D, Adelman D, et al. Allergen skin tests and free IgE levels
during reduction and cessation of omalizumab therapy. J Allergy Clin Immunol. 2008;121(2):506-11.
19) Nopp A, Johansson SG, Ankerst J, Palmqvist M, Oman H. CD-sens and clinical changes during withdrawal of
Xolair after 6 years of treatment. Allergy. 2007;62(10):1175-81.
20) Chang TW, Wu PC, Hsu CL, Hung AF. Anti-IgE antibodies for the treatment of IgE-mediated allergic diseases.
Adv Immunol. 2007;93:63-119.
21) Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients
with allergic asthma. Allergy. 2009;64(12):1728-36.
22) Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations predict excess lung function decline in
asthma. Eur Respir J. 2007;30(3):452-6.
23) Braunstahl GJ, Leo J, Thirlwell J, Peachey G, Maykut R. Uncontrolled persistent allergic asthma in practice:
eXpeRience registry baseline characteristics. Curr Med Res Opin. 2011;27(4):761-7.
24) Molimard M, Mala L, Bourdeix I, Le Gros V. Observational study in severe asthmatic patients after
discontinuation of omalizumab for good asthma control. Respir Med. 2014;108(4):571-6.
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Experience. J Allergy Clin Immunol.133(2):AB2.
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27) Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV. American Academy of Allergy,
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omalizumab-associated anaphylaxis. J Allergy Clin Immunol. 2007;120(6):1373-7.
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Adv Respir Dis. 2014;8(4):103-10.
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67

(Diagnosis and treatments of Asthma-COPD Overlap Syndrome: ACOS)

Global Initiative for Asthma (GINA) 2015 ACOS
noxious particles gases fixed airflow obstruction asthma-like
inflammation COPD-like inflammation 1
COPD biomass
nonsmoking COPD 2 Global Initiative for Chronic Obstructive
Lung Disease (GOLD) COPD
(asthma and COPD co-exist) anti-inflammatory drugs

3
Asthma and COPD Overlap Syndrome (ACOS)
Asthma-COPD overlap syndrome (ACOS)

( 40 )
incomplete reversible airflow obstruction COPD
(episodic breathlessness) (atopy) eosinophils
ACOS (specificity) asthma COPD
chronic bronchitis emphysema HRCT
asthma reversible airflow obstruction
COPD (short term bronchodilator
reversibility) TORCH UPLIFT COPD reversible airflow obstruction
Gibson Simpson Asthma-COPD overlap syndrome COPD
variability of airflow obstruction incompletely reversible airflow obstruction
FEV1
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COPD reversibility UPLIFT COPD 66%

(ipratropium salbutamol) FEV1 15%4
ACOS 13-21% obstructive airway diseases5, 6
Asthma-COPD overlap syndrome

Soler Cataluna ACOS 2012 major
criteria 3 minor criteria 3 ACOS major criteria 2 minor criteria 2 7
Major criteria
1) FEV1 >15% 400 ml
2) Sputum eosinophilia
3) asthma ( 40 )
Minor criteria
1) Elevated serum total IgE
2) History of atopy
3) FEV1 >12% 200 ml 2
Zeki ACOS
6
1) asthma partially reversible airflow obstruction bronchodilators
pulmonary emphysema carbon monoxide diffusing capacity (DLCO) 80% predicted
2) COPD pulmonary emphysema reversible or partially reversible airflow
obstruction environmental allergy DLCO
Samuel Louise major criteria ACOS 5
1) asthma COPD
2) atopy hay fever elevated serum total IgE
3) 40
4) 10 pack years
5) post bronchodilator FEV1 <80% predicted FEV1/FVC ratio <0.7
minor criteria FEV1 >15% FEV1 >12% 200 ml
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Asthma

Asthma COPD overlap syndrome

COPD
Atopy

Triggers
Cigarette smoking
Biomass exposure
Smooth Muscle dysfunction
Small Airway inflammation and repair
Inflammatory cell infiltration

Mucosal edema
Epithelial damage
Mucus hyper-secretion
Basement membrane thickening
Bronchoconstriction
Abnormal bronchial hyper-reactivity
Smooth muscle hyperplasia
& hypertrophy
Inflammatory mediator release
(Symptoms and Exacerbation)

Asthma & COPD overlap syndrome ( 5)
severe asthma, ACOS
COPD
Asthma (severe)
ACOS
COPD
> 40
> 40 (50-65 )
> 65
>
Varied
>
Nonsmoker
Past or current smoker or Past or current smoker or
or smoking < 5 pack y
smoking > 10 pack y
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smoking > 10 pack y
70
Atopic present
Atopy present
No atopy
Frequent SABA use
Exercise very limited
Exercise very limited
Exercise limitation in
Frequent SABA use
between attack
Oxygen dependence
Dependent on OCS
(co- Rhinosinusitis
morbidities)
Obesity
Rhinosinusitis
GERD
GERD
Coronary artery disease
GERD
Metabolic syndrome
Frequent exacerbation
Frequent exacerbation>
COPD
Exacerbation and exercise

intolerance
Intermittent to chronic
moderate to severe
airflow limitation
Intermittent to chronic
moderate-severe airflow
chronic moderate-severe
airflow limitation (GOLD II-IV)
limitation
FEV1/FVC <0.7
FEV1/FVC <0.7
FEV1/FVC <0.7
FEV1< 68% predicted,
FEV1< 68% predicted,
Static &dynamic
FEV1 or <65% after
FEV1 or <65% after
hyperinflation
SABA
SABA
DLCO normal
DLCO normal or low
DLCO <80% predicted
FENO > 50 ppb
FENO > 25-50 ppb
FENO < 25 ppb
Sputum eosinophils 3% Static hyperinflation

Exacerbation >3/y
Exacerbation > 3-5/year
2559
Exacerbation >2/year when

FEV1< 50% predicted
71
Frequent nocturnal
Infrequent wakening
awakening 4 /week
Pulm hypertension (late)
Airway inflammation :
Airway inflammation :
Airway inflammation
eosinophils> neutrophils
eosinophils
neutrophils > eosinophils
Mast cells
neutrophils & CD4+ T
Mast cells?
CD4+ lymphocyte
lymphocytes
CD4+ T lymphocytes &
Basement membrane
CD8+ T lymphocytes
CD8+ T lymphocytes
thickening
Alveolar macrophages,
Smooth muscle
Alveolar macrophages
Smooth muscle
hyperplasia/ hypertrophy hyperplasia/hypertrophy

No emphysema
Emphysema
Peribronchiolar fibrosis
Mediators
/cytokines
IgE, IL-4, IL-5, IL-13,

eotaxin
Peribronchiolar fibrosis
IgE ,IL-4, IL-5, IL-13,IL1, IL-8, IL-6, TNF-,
Emphysema with alveolar

destruction
IL-1, IL-8, IL-6, TNF-,
protease
eotaxin, protease
severe asthma, COPD ACOS ( 6)
difficult to control (severe) asthma 20%
COPD ACOS 6 difficult to control asthma
overlap feature
(aged lungs) (co-morbidities) cardiovascular disease
osteoporosis metabolic diseases diabetes co-morbidities
allergic rhinitis gastroesophageal reflux disease (GERD)
(adherence)
(inhaler device techniques)

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72
(physical impairment) (cognitive impairment)

ACOS asthma COPD
asthma COPD ACOS
ACOS COPD
1) ACOS COPD 8
2)
(poor quality of life)9
3) (exacerbation)
(isolated asthma)10
(isolated COPD) 11
4) (direct healthcare cost utilization)12
ACOS
National Asthma Education and Prevention Program (NAEPP EPR3)13 GINA guideline1 COPD GOLD guideline3
controller medications ICS,
ICS-LABA, LTRA, theophylline omalizumab rescued medications SABA,
SAMA oral prednisolone maintenance therapy COPD LAMA
tiotropium, LABA, ICS-LABA roflumilast theophylline triple therapy ICSLABA-LAMA COPD 14 asthma-COPD overlap syndrome
GINA guideline GOLD guideline guideline
COPD asthma Canadian COPD Guideline
COPD asthma component inhaled corticosteroid
15 HRCT COPD phenotypes
Fujimoto Japanese COPD Guideline COPD
asthma 16 Spanish COPD guideline COPD B
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73
mixed COPD and asthma severity I II

inhaled corticosteroid LABA severity III IV ICS-LABA-LAMA
theophylline PDE4 inhibitors 17
(Non-pharmacological therapy)
(Smoking cessation)
(pack years) ACOS COPD
ACOS COPD

18
15-25
5 %
ICS
nicotine replacement therapy (NRT) non-nicotine medication
bupropion varenicline 15% 24%
nicotine replacement therapy (NRT) non-nicotine medication
ACOS
5
(Pharmacological therapies)
ACOS
1. Board spectrum pharmacological therapies
2. Narrow spectrum pharmacological therapies
1. Board spectrum pharmacological therapies COPD
ACOS
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74
1) (relievers) short acting bronchodilators short acting 2

agonists (SABA) short acting muscarinic antagonist (SAMA)
SABA as needed basis tolerance
down regulation receptors
controller inhaled corticosteroid
COPD ipratropium salbutamol
12 19 GOLD SAMA SABA
(regular basis) 3 SABASAMA combination
COPD combination SABA-SAMA
19 ACOS
SAMA
2) (long acting bronchodilators LABD)
2.1 (long acting 2 agonists) LABA
LABA LABA monotherapy
exacerbation 20 (black box warning)
(US FDA) LABA inhaled
corticosteroid (ICS) LABA (anti-inflammatory effect)
ICS-LABA ICS
LABA LABA ICS 1
LABA (LABA safety) ICSLABA combination LABA LABA
LABA
LABA 21
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75
LABA LAMA COPD

(first line treatment)
(more symptoms and low risk) GOLD stage I II COPD
B LABA COPD
LABA 3
LABA ACOS POET
COPD moderate to severe LABA salmeterol tiotropium
ICS
ICS (baseline FEV1),
sputum eosinophilia ACOS
FEV1 22, 23 LABA
LAMA ACOS LABA ACOS
2.2 (long acting muscarinic
antagonists) LAMA LAMA tiotropium (first line treatment)
COPD GOLD
stage II-IV ICS, LABA theophylline4
COPD B, C D GOLD3
LAMA
LAMA tiotropium ICS TALC
52 tiotropium ICS peak flow rate
, pre-bronchodilator FEV1 tiotropium ICS

ICS salmeterol ICS tiotropium
ICS pre-bronchodilator FEV1 salmeterol ICS 24
tiotropium ACOS (extrapolation)
12 tiotropium
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76
placebo COPD concomitant asthma baseline FEV1 80% predicted

tiotropium AUC FEV1 0-6 pre-dose
FEV1 COPD asthma placebo23
48 tiotropium Respimat ICSLABA FEV1 80% predicted tiotropium
FEV1 (delayed time to first exacerbation)
placebo 226 282 tiotropium25, 26

COPD (low FEV1) ACOS
tiotropium LAMA tiotropium

ACOS
3) (inhaled corticosteroid ICS ) ICS

Th2 mediated inflammation
ICS
asthmatic controller
(cost effectiveness)
1 COPD ICS ICS
COPD FEV1
COPD FEV1
50% 60% predicted GOLD
ICS-LABA C D COPD
FEV1 (GOLD stage) 3
ICS-LABA COPD (pneumonia)27
asthma ICS
ICS ACOS sputum
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77
eosinophilia asthma-COPD overlap ICS

fluticasone proprionate 3 FEV1 sputum eosinophilia
ICS28
GOAL ICS-LABA fluticasone
proprionate salmeterol 1

ICS-LABA

ICS (well controlled and total controlled asthma) ICSLABA 10

pack-years ACOS29
4) triple therapy (ICS-LABA-LAMA) (triple therapy)
COPD LAMA ICS-LABA
ICS-LABA LAMA COPD GOLD guideline
LAMA-ICS-LABA combination (additional benefit)
OPTIMAL moderate to severe COPD 1 COPD
tiotropium fluticasone salmeterol tiotropium salmeterol
tiotropium placebo triple therapy
30
budesonide formoterol COPD tiotropium 3
31 COPD UPLIFT
ICS triple therapy LAMA-ICS-LABA 4
Triple therapy (LAMA-ICS-LABA) ACOS
ACOS ICS resistance
ICS asthma, COPD ACOS
ICS resistance ICS
32
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78
2. Narrow spectrum pharmacological therapies ACOS

Narrow spectrum treatment ACOS leukotriene
modifiers leukotriene receptor antagonist 5-lipoxygenase monoclonal antibody
IgE
1) Leukotriene receptor antagonist (LTRA) LTRA ICS
ICS first line GINA step 2 controller
GINA LTRA ICS
LTRA ICS
cystenyle leukotriene pathway LTRA exercise
induced bronchospasm aspirin induced asthma
ACOS
LTRA COPD
LTRA ACOS5
2) Omalizumab DNA-derived humanized monoclonal murine antibody IgE
IgE mast cells basophils allergic inflammation
exacerbation IgE asthma
atopy 33 omalizumab serum IgE 30-700
IU/ml skin prick test in vitro perennial antigen
ICS ICS-LABA 34 INNOVATE study
omalizumab primary endpoint
ICS high dose ICS-LABA exclude
10 pack years ACOS
omalizumab COPD atopy
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79
ACOS atopy IgE

omalizumab
ICS-LABA
LAMA selective PDE4 inhibitors roflumilast omalizumab
ACOS
Broad spectrum treatment COPD ACOS
1) ICS-LABA-LTRA ICS-LABA-LAMA ICSLABA-LTRA open label study
ICS-LABA
added on montelukast
ACT score 3 6 allergic rhinitis

ACOS35
ICS-LABA
ICS
COPD
FEV1 50% predicted GOLD ICS-LABA-LAMA
ICS-LABA COPD LAMA
ICS-LABA
3
asthma NAEPP EPR3
ICS LTRA airway
inflammation COPD asthma feature Long acting
bronchodilators (LABD) LABA LAMA
chronic bronchitis COPD
asthma LAMA GOLD
2559
80
guideline FeNO (>50 ppb) sputum eosinophil count (>3%)

ICS (Eosinophilic phenotypic approach)
2) Selective PDE4 inhibitors roflumilast selective PDE4 inhibitors PDE4
cyclic AMP add on therapy ICS-LABA
LAMA moderate to severe COPD chronic bronchitis
roflumilast placebo COPD LABD
LABA LAMA post-hoc
ICS pre-clinical pharmacology COPD sputum
neutrophils sputum eosinophils 36 COPD sputum eosinophilia
ACOS roflumilast ACOS Spanish
COPD guideline PDE4 inhibitor triple therapy (ICS-LABA-LAMA)
COPD overlap asthma phenotype (severe) IV (expectoration)
3) Theophylline Theophylline nonselective PDE inhibitor COPD
GINA ICS ICS
COPD GOLD theophylline

theophylline LABA salmeterol theophylline
corticosteroid resistance COPD corticosteroid resistance
3 ACOS
theophylline theophylline ACOS
4) Oral prednisolone uncontrolled asthma step 5 GINA guideline
low dose prednisolone COPD
oral corticosteroid
severe asthma

ACOS rhinitis sinusitis allergic
bronchopulmonary aspergillosis COPD
oral prednisolone selective
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81
PDE4 inhibitor roflumilast oral corticosteroid

ACOS ACOS ACOS

severe asthma COPD
Asthma (severe)
First-line
pharmacotherapy
and nonpharmacologic RX
Current add-on
Pharmacotherapy
ICS
ICS + LABA
Allergen avoidance
Emerging
treatments
Asthma-COPD Overlap
Syndrome (ACOS)
ICS LAMA LABA
Smoking cessation
Pulmonary rehabilitation
LABA,
LAMA,
LTRA, or
Roflumilast or Theophylline,
Omalizumab
Prednisone
Anti-IL-5, anti-IL-13
Refer to asthma and COPD
ICS+LABA once daily emerging treatments
Azithromycin
Consider using FeNO to
endotype and phenotype
Vaccines
Bronchial thermoplasty Bronchial thermoplasty
LABA,
LTRA
Theophylline
Omalizumab
Prednisone
LAMA
COPD
Bronchodilators
LAMA or LABA or both
Smoking cessation
Pulmonary rehabilitation
ICS or
Roflumilast
Theophylline
LAMA + LABA once daily

Carbocisteine,Azithromycin
Anti-IL8, p39 kinase
inhibitors
Endobronchial valves
Endoscopic or
Lung volume reduction
surgical treatment
surgery (LVRS)
Lung transplantation
asthma, COPD ACOS first line treatments, added on
treatments emerging treatments 6
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82
ACOS
-
- total IgE specific IgE perennial antigens
- allergic bronchopulmonary aspergillosis (ABPA) high resolution CT scan
(HRCT) bronchiectasis Allergic bronchopulmoanry aspergilosis
(ABPA)
- oral prednisolone oral
corticosteroid trial 2
FEV1 FeNO 50% corticosteroid
responsive oral corticosteroid trial ICS-LABA combination
- LAMA tiotropium 2
dual bronchodilators (LABD) LABA
LABA LABA LAMA SAMA

- LTRA montelukast
allergic rhinitis 2-6
- low dose sustained release theophylline 5-10 mg/L
2-6
- roflumilast COPD exacerbation
minimal clinical important
difference
- omalizumab
allergic test skin prick test specific IgE perennial
2559
83
antigen serum total IgE 30-700 IU/L 16

- sputum induction bronchial biopsy eosinophilic airway
inflammation
asthma COPD

Asthma-COPD overlap syndrome (ACOS) asthma COPD
20%
obstructive airway diseases ACOS
asthma COPD
ACOS fixed airflow obstruction
atopy
eosinophils
ACOS

ACOS asthma
COPD biomarkers phenotypes
exhaled nitric oxide
ACOS

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87

(Preschool wheezing: which one is asthma?)

(wheeze)

acute bronchiolitis pneumonia
respiratory syncytial virus (RSV)

1. (Heterogeneity of preschool
wheezing)

2538 Martinez FD 1
1,246 Tucson Children's Respiratory birth cohort 6
51.5 6 (Never wheeze) 33.5
1 3 3
2 ( 60) 6 (Transient early
wheeze) ( 40) 6 (Persistent wheeze)
Transient early wheeze
(lung function)
6
Never wheeze Persistent wheeze total IgE
6 6
Transient early wheeze ( 1)
16 2 Transient early
Persistent wheeze
6 16
2559
88
6 ( 1)
2
6-16
Transient early wheeze ( 3
6 ) 75
Persistent wheeze ( 50-60) 16
1 z-scores height-adjusted maximal expiratory flow 2.4 6 11 16

4 preschool wheeze phenotypes Never wheeze (
6 ) Transient early wheeze ( 3 )
Late onset wheeze ( 6 ) Persistent wheeze (
3 6 )
wheezing phenotypes
/ (Transient
early, Late-onset Persistent) (Episodic viral Multitrigger) (Atopic Non-atopic) latent class
analysis wheezing phenotypes
2
(transient wheeze)
2559
89
(persistent wheeze)
2
transient wheezer ()
persistent wheezer ( )

2. (Asthma prediction tools)
2.1 Asthma Predictive Index (API)
API .. 2543 CastroRodriguez JA 4 Tucson Children's Respiratory Study
non-selective birth cohort
13
6 8 11 13 3 API
(major criteria) ( atopic
dermatitis, AD) (minor criteria)
(wheeze unrelated to colds) (allergic rhinitis, AR) eosinophil
4 ( 1)
API 2 1) API (positive loose API)
1 2 2) API
(positive stringent API) (frequent wheezing) 1
2 frequent wheeze wheeze rating scale 3 1 (
) 5 ()
positive loose API 6-13 negative loose
API 4 positive stringent API 6-13
negative stringent API 7 API positive
predictive value (PPV) 3 positive stringent API
42-77
6-13 negative predictive value (NPV)
3 negative stringent API 84-92
API API
2559
90
.. 2554 Leonardi NA
5 API Leicestershire Cohort non-selective
cohort Tucson cohort eosinophil

original API .. 2543 PPV stringent API 7-10
( 35-40) NPV 92
2.2 Modified Asthma Predictive Index (mAPI)
.. 2547 Guilbert TW 6 API modified API (mAPI)
Preventing Early Asthma in Kids (PEAK)
(inhaled fluticasone)
mAPI (positive mAPI) mAPI API
sensitization (aeroallergen) ( ) API

sensitization 4 12
( 1)
.. 2556 Chang TS 7 mAPI
COAST high-risk birth cohort
(skin test)
6-11 30 3
mAPI 6-11 89-96 (PPV) NPV
71-74 mAPI
3 2
1
mAPI
30 11
Tucson Children's Respiratory Study original API
3 mAPI 6-11
70-87 PPV original API NPV 91
2559
91
original API
predictive values PPV
PPV
2.3 University of Cincinnati Asthma Predictive Index (ucAPI)

.. 2557 Amin P 8
University of Cincinnati API (ucAPI)
original API mAPI 2 12
3 original API eosinophil
sensitization ( )
mAPI ( 1) ucAPI Cincinnati Childhood Allergy and Air
Pollution Study
7 17.5
3 ucAPI 7 60 NPV
89 PPV NPV original API
.. 2543
ucAPI atopic persistent wheeze
( 2 12 2 3
) 7
PPV 71 NPV 85
1 (Asthma predictive indices)

API

( )
3
Loose: Early wheezer
( )
Stringent: Early frequent
wheezer (
, wheeze
rating scale 3)

( 1 )
-
()
-
()
2559

( 2 )
-

- eosinophil
4
-
()
Modified
API (mAPI)
2-3
University 3
of
Cincinnati
API (ucAPI)
-
4 12 ()
( -
24 .
1 ()
)
- Sensitization

1
-
2 12 -
( 3 )
- Sensitization

1
92
-

- eosinophil
4
- Sensitization

-

-
()
- Sensitization
2.4 Isle of Wight cumulative risk score

.. 2546 Kurukulaaratchy RJ 10 persistent
wheeze Isle of Wight birth cohort
4 ( 37 10 )
Isle of Wight cumulative risk score 4
2 1
4 1 4
10 3
PPV 68 NPV 75 4
83 NPV 64
2.5 PIAMA risk score
.. 2552 Caudri D 11

1-4 Prevalence and Incidence of Asthma and Mite Allergy cohort (PIAMA, The
Netherlands)
2559
93
12 7-8 11 PIAMA
risk score 4 8

2 55 < 10
3 7-8 20 PPV 23
NPV 94 30 42
NPV 91
2 PIAMA risk score

(A)
(B)
1 (C)
1 (D)
(1-3 ) (E)
( 4 ) (F)
(G)
(1-2 ) (H)
( 3 ) (I)
(J)

( )
4.6 x A ( = 1, = 0) +
7.3 x B ( = 1, = 0) +
4.2 x C ( = 1, = 0) +
7.7 x D ( = 1, = 0) +
4.2 x E ( = 1, = 0) +
9.1 x F ( = 1, = 0) +
7.1 x G ( = 1, = 0) +
4.6 x H ( = 1, = 0) +
6.9 x I ( = 1, = 0) +
8.2 x J ( = 1, = 0)
11
2.6 Leicester prediction tool

.. 2557 Pescatore AM 12
1-3 Leicestershire cohort
12
5 28 Leicester
10
2559
94
3 15
5 5 PPV
49 NPV 86 10 79 NPV
76 >13 89
3 Leicester prediction tool12

( )
(A)
A ( = 1, = 0) +
(B)
B (1 = 0, 2 3 = 1) +
12 C ( = 0, =1) +
(C)
12 D (0-3 = 0, > 3 = 2) +
(D)
12 (E) E ( = 0, = 1, = 2) +
(F)
F ( = 0, = 2, = 3) +
G ( = 0, = 1) +
12 (G)
H ( = 0, = 1) +
12 (H)
(I)
I ( = 0, = 1) +
(J)
J ( = 0, = 1, = 1)
12
2.7

(biomarkers)
2559
95
.. 2558 Klaassen EM 13 2-4

API (volatile organic compounds,
VOCs) (exhaled breath) (gene expression)
(peripheral blood mononuclear cell, PBMC)
eosinophil specific IgE
0.35 kU/L eosinophil 4 API
PPV 6 60 NPV 63 API
exhaled VOCs PPV 82 NPV 83 API
exhaled VOCs Toll-like receptor-4, catalase, Tumor necrosis factor-
PBMC PPV 90 NPV 89

( ) main
outcome ( )
(
) prediction tools
API mAPI PPV

NPV

PIAMA risk score PPV
NPV PPV NPV

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96
3.

(viral-induced wheeze)

GINA (The Global Initiative for Asthma guideline) 201514
5
10
( 3 )

(
) 2-3 (low-dose inhaled
corticosteroid, ICS)

(uncontrolled) 3
(therapeutic trial) 3
short-acting 2-agonist 6-8

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97

1. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first
six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332(3):133-8.
2. Morgan WJ, Stern DA, Sherrill DL, Guerra S, Holberg CJ, Guilbert TW, et al. Outcome of asthma and
wheezing in the first 6 years of life: follow-up through adolescence. Am J Respir Crit Care Med.
2005;172(10):1253-8.
3. Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma. J Allergy Clin Immunol.
2012;130(2):299-307.
4. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index to define risk of asthma in young
children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162(4 Pt 1):1403-6.
5. Leonardi NA, Spycher BD, Strippoli MP, Frey U, Silverman M, Kuehni CE. Validation of the Asthma Predictive
Index and comparison with simpler clinical prediction rules. J Allergy Clin Immunol. 2011;127(6):1466-72 e6.
6. Guilbert TW, Morgan WJ, Krawiec M, Lemanske RF, Jr., Sorkness C, Szefler SJ, et al. The Prevention of Early
Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education
network. Control Clin Trials. 2004;25(3):286-310.
7. Chang TS, Lemanske RF, Jr., Guilbert TW, Gern JE, Coen MH, Evans MD, et al. Evaluation of the modified
asthma predictive index in high-risk preschool children. J Allergy Clin Immunol Pract. 2013;1(2):152-6.
8. Amin P, Levin L, Epstein T, Ryan P, LeMasters G, Khurana Hershey G, et al. Optimum predictors of childhood
asthma: persistent wheeze or the Asthma Predictive Index? J Allergy Clin Immunol Pract. 2014;2(6):709-15.
9. Bacharier LB. The recurrently wheezing preschool child-benign or asthma in the making? Ann Allergy Asthma
Immunol 2015;115(6):463-70.
10. Kurukulaaratchy RJ, Matthews S, Holgate ST, Arshad SH. Predicting persistent disease among children who
wheeze during early life. Eur Respir J. 2003;22(5):767-71.
11. Caudri D, Wijga A, CM AS, Hoekstra M, Postma DS, Koppelman GH, et al. Predicting the long-term prognosis
of children with symptoms suggestive of asthma at preschool age. J Allergy Clin Immunol. 2009;124(5):90310 e1-7.
12. Pescatore AM, Dogaru CM, Duembgen L, Silverman M, Gaillard EA, Spycher BD, et al. A simple asthma
prediction tool for preschool children with wheeze or cough. J Allergy Clin Immunol. 2014;133(1):111-8 e1-13.
13. Klaassen EM, van de Kant KD, Jobsis Q, van Schayck OC, Smolinska A, Dallinga JW, et al. Exhaled
biomarkers and gene expression at preschool age improve asthma prediction at 6 years of age. Am J Respir
Crit Care Med. 2015;191(2):201-7.
14. Global initiative for asthma. Global strategy for asthma management and prevention (2015 update). 2015
[updated April 1, 2015]; Available from: http://www.ginasthma.org.
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99
Small airway diseases in asthma: Is it really that small?

small
airways
nocturnal
asthma1 small airway function early airway closure
severe asthma exacerbation2
Pathology of small airways in asthma

lung resection specimen large small
airways T cells eosinophils
3, 4 activated eosinophils IL-5
mRNA small airways 4,5
inflammatory cells inflammatory cells small airways
airway smooth muscle alveolar attachment (outer area )
inflammatory cells basement membrane smooth
muscle (inner area )6 cystic fibrosis
inflammatory cells small airways peripheral airway obstruction
6
nocturnal asthma alveolar tissues
eosinophils CD4+ lymphocytes 4 am 4
pm lung function impairment 1, 7
corticosteroids
corticosteroids glucocorticoid receptor (GR)-binding affinity8
GR (GR corticosteroids) T
lymphocytes, eosinophils , macrophages neutrophils small
airways steroid resistant severe asthma fatal asthma9
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100
small airways peripheral airway obstruction

severe asthma small airway inflammation uncoupling airways lung
parenchyma( airways lung parenchyma) tethering force
alveolar attachment small airways
small airways airway wall remodeling
airway narrowing airway smooth muscle shortening10
small airways lung recoil
airway hyperresponsiveness (AHR) remodeling
subepithelial fibrosis smooth muscle mass11 fibroblasts
small airways differentiation myofibroblasts
TGF- fibroblasts fibroblasts large airways12
fibroblasts small airways
airway fibrosis small airways
small airways
small airways fatal asthma eosinophils small airways
nonfatal asthma13, 14 severe asthma neutrophils lung parenchyma
moderate asthma15 severe asthma air trapping
16
Assessment of small airway inflammation

small airways
1. Fractional exhaled nitric oxide (FENO) FENO small
airway function FENO phase III slope single N2 breath washout
curve small airway function17 FENO small airway inflammation
FENO large small airways
airway NO alveolar NO 18
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101
nitric oxide conductive airways alveoli19,

20
alveolar nitric oxide air trapping RV/TLC
premature airway closure21 alveolar NO

distal airway inflammation NO
endothelial cells mechanical stress airway closure
opening
2. endothelin 1, eotaxin-1 RANTES hydrogen peroxide
exhaled breath condensate22-25
Physiology of small airways

Small airways ( 2 mm) flow
total airway resistance 1026, 27 small airway obstruction
mechanical properties lungs collateral ventilation
bypass small airway obstruction
ventilation distribution28 single-breath nitrogen washout
curve29 small airways beads nitrogen concentration
alveolar plateau curve alveolar gas composition
alveolar spaces uniform ventilation small airway
obstruction alveolar gas composition uniform alveolar plateau
curve nitrogen concentration29 expired alveolar gas
low nitrogen high oxygen concentration alveolar gas wellventilated alveoli alveolar gas high nitrogen low
oxygen concentration collaterally ventilated alveolar space29
total cross-sectional area small airways large airways airway flow
small airways large airways gas velocity ( flow/crosssectional area) small airways laminar flow gas density
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airway resistance large airways turbulent flow gas density

airway resistance28
airways airway lining fluid small
airways
surfactant surface tension small airways
30 airway closure low lung volume
surface tension small airways small airways unstable
collapse 28 small airway closure residual volume (
) air trapping terminal bronchiole closure
surfactant inflammatory exudate excessive mucus production28
Peripheral airways resistance invasive techniques
plethysmography esophageal balloon resistance elastic recoil airways
lung volume wedge bronchoscope technique
Functional assessment of small airways

small airway obstruction premature airway closure, air
trapping, regional ventilation heterogeneity exaggerated volume dependence airflow
limitation31
Abnormal airway function smooth muscle
dynamics, airway remodeling, loss of parenchymal tethering airways
airway function airway resistance large small airways
airway resistance large small airways airway
compliance FEV1 large airway obstruction
impaired small airway function FEV1 poor correlation asthma symptoms
airway inflammation32,33 small airway impairment

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1. Impulse oscillometry (IOS)

small airway function repetitive pressure pulse
small airway resistance Mead model upper
airway artifacts small airway resistance 34 small
airway resistance IOS severe airway
obstruction oscillometric parameters
R5-R20 35 IOS airway reactance
(X5) methacholine challenge test
FEV1 PC70_X5 (
methacholine X5 70%) AHR
PC70_X5 PC20FEV136 IOS
small airway dysfunction uncontrolled asthma R5, R20, X5, Fres
AX well-controlled asthma 37 R5-R20
severe asthma mild-to-moderate asthma 20 IOS
parameters small airway impairment
ICS/LABA IOS parameters small airway
inflammation
38
marker mild asthma ICS/LABA39
R5-R20 IOS small airway resistance marker

ICS ciclesonide small airways
ICS ciclesonide small airway
function inflammation fluticasone propionate40 HFA-BDP
small airway function CFC-BDP41 ICS
small airways small airway resistance
normal spirometry42 IOS allergic
rhinitis AHR methacholine challenge test peripheral
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airway obstruction 43

salmeterol tiotropium FEV1 44 bronchodilation
effect 45 IOS parameters
methacholine chest tightness
dyspnea spirometry wheeze46
2. Lung clearance index (LCI)
concentration curve multiple-breath N2 washout early
small airway marker bronchoprovocation
LCI convection (Scond) diffusion-dependent ventilation
heterogeneity (Sacin)47 markers
ventilation heterogeneity ( degree of small airway obstruction) markers
LCI, Scond , Sacin detect ventilation heterogeneity
3. Ventilation heterogeneity
multiple-breath N2 washout (MBW) ventilation
distribution conductive acinar spaces MBW
tidal volume 1 L
functional residual capacity (FRC)
100% oxygen inspiratory bag 20-25
residual volume
FRC progressive N2 dilution N2 concentration tracing ( 1)
plot graph semi- logarithmic scale N2-washout curve
graph % mean expired N2 concentration breath initial N2 concentration
N2-washout curve y-axis log[N2] x-axis lung turnover
(expired volume/FRC) lung turnover different lung volume
dilution MBW normalized alveolar slope (S) (
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105
N2 concentration difference O2 mean

alveolar N2 inspired concentration) ( 2) ventilation inhomogeneity
ventilation inhomogeneity 2 1) convection-dependent ventilation
inhomogeneity ( convection flow lung unit
pressure-volume lung unit ) convection
lung unit ventilation emptying air
positive alveolar N2 slope gravity-dependent flow
upper lung unit lower lung unit 2) diffusion-convection-dependent inhomogeneity
convective diffusive gas transport asymmetry lung structure
interaction diffusion convection (asymmetry airway
narrowing lung volume asymmetry peripheral lung zones acinar
levels bronchial tree) S curve value 2 2 1) S curve
diffusion-convection interaction value plateau
Sacin acinar ventilation heterogeneity 2) S curve convectiondependent ventilation value Scond
conductive ventilation heterogeneity histamine
Scond Sacin
(small airways) proximal acinar zone48 Scond
inhomogeneous narrowing conductive airways ventilation difference
asynchronous emptying methacholine Scond
histamine FEV1 histamine49
baseline ventilation heterogeneity
AHR 50
airway inflammation Scond AHR methacholine
airway inflammation Scond inhaled
corticosteroids 50
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1 N2 concentration volume tracing48
2 Sacin Scond normalized alveolar slope48

4. Lung function assessment
premature airway closure air trapping RV TLC
RV/TLC best measure RV air trapping31 RV/TLC
upper normal limit % predicted31 RV/TLC % predicted
severe asthma air trapping 51 RV/TLC
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FVC lung volume

FVC marker air trapping validation
COPD51 air trapping TLC % predicted FVC
% predicted FVC air trapping
small airway disease residual volume (RV),
FVC normal FEV1/FVC ratio
5. Ventilation imaging
Noninvasive imaging regional ventilation hyperpolarized 3He 129Xe
MRI52 non-ionizing radiation gas
3He 129Xe inert nontoxic inhaled contrast agent detect
MRI 3He 129Xe 3He signal 129Xe high resolution
ventilation airway space 52 129Xe gas
exchange airspace 3He 53 uniform signal
gas
obstructive lung
disease asthma COPD dark area ventilation defect
mucus plugging, structural airway defects airway narrowing ventilation
defects 54 3He MRI
small airways ventilated nonventilated airways
baseline methacholine
challenge salbutamol heterogeneity poorly
ventilated areas peripheral lung zone 70 small airways
ventilation defects 55
small airways
baseline Scond Sacin
small airway markers ventilation heterogeneity inhaled
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corticosteroids asthma control 56

small airway function
airway inflammation fraction of exhaled nitric oxide
small airway inflammation small airways noneosinophilic
inflammation noninflammatory component airway edema
ventilation heterogeneity persistent small airway dysfunction
high dose ICS57
ventilation heterogeneity small airways
small airway dysfunction airway caliber
small airways work of breathing ventilation heterogeneity
peripheral lung zone airway closure bronchoconstriction58
respiratory system stiffness59 60

recurrent asthma exacerbations small
airway closure2 air trapping60 small airway dysfunction
ventilation heterogeneity airway closure
airway closure ventilation heterogeneity
RV/TLC
Sacin ventilation heterogeneity distal airways ICS61
airway closure poorly ventilated lung
units
baseline Scond
(ICS dose uptitration)
Sacin ICS dose downtitration
62 ventilation
heterogeneity ongoing airway inflammation lung periphery
small airway dysfunction
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ICS ventilation heterogeneity

deposition ICS proximal airways distal airways
ventilation heterogeneity proximal conductive
airways ( baseline Scond ) ICS
ICS ventilation heterogeneity distal
airway ( baseline Sacin ) ICS
ICS distal airways proximal
airways
Asthma exacerbation GINA
guideline recurrent exacerbations
small airways 2 early airway closure high lung volume
closing volume (CV) closing capacity (CC) single-breath nitrogen
washout CV CC severe asthma exacerbations2 CV
CC small airway obstruction FEV1, PEF
variation RV/TLC 2 2 small airway
pathology
1) CV CC
2) functional impairment peripheral lung zone
exacerbations difficult-to-control asthma small
airway narrowing contractile latch state airway smooth muscle
3) airway closure
lung volume small airway obstruction
severe asthma exacerbation2, 31
Small airway abnormalities elderly asthma / fixed
airflow obstruction small airway obstruction elderly
asthma elderly asthma younger
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asthma poor response small airway dysfunction63

lung function elderly asthma lung function younger
asthma64 fixed airflow obstruction65-67 physiologic change
elastic fiber peripheral airways68, 69 supporting
tissues airway trapping, small airway collapsibility premature
small airway closure small airway obstruction
elderly asthma air trapping
RV/TLC 66
severe asthma small airway involvement small
airway inflammation autopsy, transbronchial lung biopsy, alveolar NO levels
small airway function premature airway closure, air trapping, decreased airway
reversibility63
smoking asthma small airway involvement
small airways structural
change63

Small airway abnormalities pathobiology
small airway obstruction
ventilation heterogeneity, air trapping, premature airway closure
severe exacerbation severe asthma 1) small
airway dysfunction asthma phenotypes
severe asthma, elderly asthma / fixed airflow obstruction smoking
asthma 2) small airway dysfunction asthma phenotypes
ICS ICS/ LABA extra-fine formulations
biomarkers/ parameters peripheral airways 61, 70-72 specific
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asthma phenotypes small airways 1)

pathology function small airways 2)
specific asthma phenotypes small airway
abnormalities 63

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52. Johnson JR, Hamid Q. Appraising the small airways in asthma. Curr Opin Pulm Med. 2012;18:23-8.
53. Mugler JP, 3rd, Altes TA, Ruset IC, Dregely IM, Mata JF, Miller GW, et al. Simultaneous magnetic
resonance imaging of ventilation distribution and gas uptake in the human lung using hyperpolarized
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airways in the clinical expression of asthma in adults. J Allergy Clin Immunol. 2012;129:381-7, 7 e1.
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the lung periphery. J Allergy Clin Immunol. 2006;118:340-6.
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64. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in
adults with asthma. N Engl J Med. 1998;339:1194-200.
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obstruction and reversibility in adult patients with asthma. Chest. 1998;114:1336-42.
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physiologic outcomes in elderly nonsmokers. Am J Respir Crit Care Med. 2000;162:1423-8.
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2003;40:317-21.
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Comparison with normal and emphysematous lungs. 1. Structural aspects. Chest. 1992;101:793-9.
70. Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paterno A, et al. Effects of extra-fine inhaled
beclomethasone/formoterol on both large and small airways in asthma. Allergy. 2010;65:897-902.
71. Cohen J, Douma WR, ten Hacken NH, Vonk JM, Oudkerk M, Postma DS. Ciclesonide improves measures
of small airway involvement in asthma. Eur Respir J. 2008;31:1213-20.
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assessment with functional helical thin-section computed tomography. J Allergy Clin Immunol.
1999;104:S258-67.
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(Allergen-specific immunotherapy for childhood asthma)

76-981

(natural course)

(immunotherapy)
2
(new allergic sensitizations)
(allergic rhinitis)
(allergic rhinitis with asthma)

(antigen)
antibody

(allergen)
IgE-mediated immune response
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118
protective immune response

immune tolerance
immune tolerance 3 ( 1)
1. (Cellular immunity)
(aeroallergen)
IgE-mediated immune response helper T (Th)

cells 2 high-dose (
) (subcutaneous) (sublingual)
helper (Th) cells 2 1 (shift of T-cell polarization from Th2 to
Th1)3 regulatory T cells (Treg)
cytokine 4,5 Th1 (IFN-, IL-12)
Treg (IL-10, TGF-) Th2 cytokines (IL-4, IL-5, IL-9, IL-13)
cytokine
IL-10 TGF- (mast cell),
eosinophil, basophil
maturation dendritic cell antigen-presenting cell
Th2 IL-10 TGF-
Th2
IL-9 growth factor (mast cell)
desensitization (mast cell)
IL-13 (mucus)
2. (Humoral immunity)
helper (Th) cells 2 1 (shift of T-cell polarization from Th2
to Th1)3 regulatory T cells (Treg) B cell activation IL-10 TGF-
IgG, IgG4, IgA (allergen-specific)
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119
T cell
Th1
Th2
Tr
eg
IL-4, IL-5, IL-9, IL-13

IFN-
IL-10
TGF-+
B cell
IgG
IgG4
IgA
IgE
Eosinophil
Mast
Basophil
1 6
B cell activation Th2 IgE
FcRI (mast cell) basophil sensitization
(allergen) complex IgE cross-linking degranulation
basophil inflammatory mediator
IgG4, IgA
(blocking antibody)7 Ig-allergen complex IgE basophil

degranulation
3. (Effector cell recruitment)
2 early late
response early response degranulation (mast cell) basophil
late response eosinophil, basophil, activated T
cells dendritic cell
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late response
8 bronchoalveolar lavage
birch pollen eosinophil, eosinophil cationic protein ( activated eosinophil)

late response Th2 cytokines IL-13
chemoattractant recruitment effector cell Treg
chemotactic factors Th29

mast cell basophil
helper (Th) cells

IgG4 blocking antibody
IgE

2 10
early,
intermediate late effect ( 2)
early phase 1 desensitization
basophil (allergen)
degranulation 10
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intermediate phase 1
helper (Th) cells 2 1 (shift of T-cell polarization from Th2 to Th1)3
regulatory T cells (Treg) IgG4 blocking antibody
IgE
late phase 1
(effector cell recruitment) IgE
(skin prick test) skin
reactivity11

(SCIT) (SLIT)
12,13 14,15
16,17

18
7019

20,21
22 (inhaled corticosteroids)20,21

exhaled nitric oxide23 peak expiratory flow (PEF)24 cochrane review
SCIT
88 3,459
42 27 10
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SCIT

2

(retrospective study) Stelmach
25 8 18 SCIT 3 5
3 50 SCIT 5
54 SCIT 3 (asthma remission)
3 (
)
systematic
review Abramsom 2 (house dust mite)

26,27
28,29

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123

systemic reactions

0.06-430
systemic reactions
31

(insect sting anaphylaxis)
31,32
1. / IgE (IgEmediated disease) (skin tests)

-
-
-
2.

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3.
(prevention of long-term disease progression)
beta-blockers

6

(autoimmune diseases)31

(immune tolerance)

1. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of
age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004;113(1):101-08.
2. Akdis CA, Akdis M. Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol. 2011;127(1):1827.
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125
3. Shamji MH, Durham SR. Mechanisms of immunotherapy to aeroallergens. Clin Exp Allergy. 2011;41(9):123546.
4. Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, et al. Grass pollen immunotherapy
inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and
increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol.
1996;97(6):1356-65.
5. Wachholz PA, Nouri-Aria KT, Wilson DR, Walker SM, Verhoef A, Till SJ, et al. Grass pollen immunotherapy for
hayfever is associated with increases in local nasal but not peripheral Th1:Th2 cytokine ratios. Immunology.
2002;105(1):56-62.
6. Eifan AO, Shamji MH, Durham SR. Long-term clinical and immunological effects of allergen immunotherapy.
Curr Opin Allergy Clin Immunol. 2011;11(6):586-93.
7. Lambin P, Bouzoumou A, Murrieta M, Debbia M, Rouger P, Leynadier F, et al. Purification of human IgG4
subclass with allergen-specific blocking activity. J Immunol Methods. 1993;165(1):99-111.
8. Rak S, Lowhagen O, Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and
eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunology. 1988;82:470-80.
9. Lockey RF, Ledford DK. Allergens and allergen immunotherapy. 4th ed. New York: Informa Healthcare; 2008.
10. Taher YA, Henricks PA, van Oosterhout AJ. Allergen-specific subcutaneous immunotherapy in allergic
asthma: immunologic mechanisms and improvement. Libyan J Med. 2010;5.
11. Tahamiler R, Canakcioglu S, Yilmaz S, Isildak H. Long-term immunotherapy for perennial allergic rhinitis:
relationship of specific IgG levels to skin-prick test results and clinical symptoms and signs. Ear, Nose, &
Throat J. 2008;87(12):E29.
12. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev.
2003(4):CD001186.
13. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, et al. Efficacy of
sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a
meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol.
2006;97(2):141-8.
14. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, Noble W, et al. Long-term clinical efficacy of
grass-pollen immunotherapy. N Eng J Med. 1999;341(7):468-75.
2559
126
15. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after discontinuation of preseasonal
grass pollen immunotherapy in childhood. Allergy. 2006;61(2):198-201.
16. Moller C, Dreborg S, Ferdousi HA, Halken S, Hst A, Jacobsen L, et al. Pollen immunotherapy reduces the
development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol.
2002;109(2):251-6.
17. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy
reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol.
2004;114(4):851-7.
18. Passalacqua G. Specific immunotherapy in asthma: a comprehensive review. J Asthma. 2014;51(1):29-33.
19. Simons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol. 1999;104:534-40.
20. Kim JM, Lin SY, Suarez-Cuervo C, Chelladurai Y, Ramanathan M, Segal JB, et al. Allergen-specific
immunotherapy for pediatric asthma and rhinoconjunctivitis: a systematic review. Pediatrics.
2013;131(6):1155-67.
21. Compalati E, Braido F, Canonica GW. An update on allergen immunotherapy and asthma. Curr Opin Pul Med.
2014;20(1):109-17.
22. Wahn U, Klimek L, Ploszczuk A, Adelt T, Sandner B, Trebas-Pietras E, et al. High-dose sublingual
immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: a doubleblind, placebo-controlled study. J Allergy Clin Immunol. 2012;130(4):886-93.e5.
23. Stelmach I, Kaluzinska-Parzyszek I, Jerzynska J, Stelmach P, Stelmach W, Majak P. Comparative effect of
pre-coseasonal and continuous grass sublingual immunotherapy in children. Allergy. 2012;67(3):312-20.
24. Zheng BQ, Wang GL, Yang S. Efficacy of specific sublingual immunotherapy with dermatophagoides farinae
drops in the treatment of cough variant asthma in children. Chinese J Contem Ped. 2012;14(8):585-8.
25. Stelmach I, Sobocinska A, Majak P, Smejda K, Jerzynska J, Stelmach W. Comparison of the long-term
efficacy of 3- and 5-year house dust mite allergen immunotherapy. Ann Allergy Asthma Immunol.
2012;109(4):274-8.
26. Mungan D, Misirligil Z, Gurbuz L. Comparison of the efficacy of subcutaneous and sublingual immunotherapy
in mite-sensitive patients with rhinitis and asthma--a placebo controlled study. Ann Allergy Asthma Immunol.
1999;82(5):485-90.
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127
27. Yukselen A, Kendirli SG, Yilmaz M, Altintas DU, Karakoc GB. Effect of one-year subcutaneous and sublingual
immunotherapy on clinical and laboratory parameters in children with rhinitis and asthma: a randomized,
placebo-controlled, double-blind, double-dummy study. Inter Arch Allergy Immunol. 2012;157(3):288-98.
28. Eifan AO, Akkoc T, Yildiz A, Keles S, Ozdemir C, Bahceciler NN, et al. Clinical efficacy and immunological
mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to
house dust mite: an open randomized controlled trial. Clin Exp Allergy. 2010;40(6):922-32.
29. Keles S, Karakoc-Aydiner E, Ozen A, Izgi AG, Tevetoglu A, Akkoc T, et al. A novel approach in allergenspecific immunotherapy: combination of sublingual and subcutaneous routes. J Allergy Clin Immunol.
2011;128(4):808-815.e7.
30. Bernstein DI, Epstein T, Murphy-Berendts K, Liss GM. Surveillance of systemic reactions to subcutaneous
immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI collaborative study. Ann Allergy Asthma
Immunol. 2010;104(6):530-5.
31. Schiappoli M, Ridolo E, Senna G, Alesina R, Antonicelli L, Asero R, et al. A prospective Italian survey on the
safety of subcutaneous immunotherapy for respiratory allergy. Clin Exp Allergy. 2009;39(10):1569-74.
32. Frew AJ. Allergen immunotherapy. J Allergy Clin immunol. 2010;125(2 Suppl 2):S306-13.
2559
2559
128
129

(Rhinosinusitis: Is it important in asthma management?)

15 1
40 75 2 35
3
(allergic rhinitis, AR) 30 6.8
4 (bronchial
hyperresponsiveness) 2.95 63
15 45
15
30 2 6

(chronic airway inflammation)
(airway hyperresponsiveness)
(wheeze)

(reversible airway obstruction)

3

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130
(sinusitis) (inflammation)
4
1. Frontal sinus:
2. Ethmoid sinus:
3. Maxillary sinus:
4. Sphenoid sinus:

pansinusitis
(rhinitis)
rhinosinusitis sinusitis

(bacterial rhinosinusitis)7

1. (nasal blockage/ obstruction/ congestion)
2. (anterior/ posterior nasal drip)

1. middle meatus (mucopurulent discharge)
/
2. (computed tomography CT scan)
ostiomeatal complex (OMC) /
7
1. (acute rhinosinusitis, ARS) 12

(viral rhinosinusitis)
10 (acute non-viral
2559
131
rhinosinusitis) 10 5

(double sickening) 12
2. (chronic rhinosinusitis, CRS)
12 (subclassification)
2.1 (CRS with nasal polyposis polyps)
2.2 (CRS without nasal polyposis polyps)

2-5 7-10
rhinovirus ( 24) influenza virus ( 11)
0.5 2 7
(plain film of paranasal sinuses)

(sensitivity)
73 (specificity) 807

1. (bacterial pathogen)

3
Streptococcus pneumoniae, Haemophilus influenzae Moraxella catarrhalis8
Streptococcal species, Anaerobic bacteria Staphylococcus aureus

Staphylococcus aureus (
36), coagulase negative Staphylococcus (CNS) ( 20) Streptococcus pneumoniae
( 17)7
Pseudomonas aeruginosa ( 16.2), gram negative bacteria ( 10.8 ) CNS (
2559
132
9.9)9
( )
anaerobic aerobic10
2. (ciliary dysfunction)

1 3
3

Streptococcus pneumoniae,
Haemophilus influenzae Pseudomonas aeruginosa
11
3. (allergy)
(AR)
/
4. (laryngopharyngeal reflux)
nasopharynx
secondary ostial obstruction mucociliary clearance
12
5. (local host factor)
natural
ostium ostium frontal sinus, ethmoid sinus maxillary
sinus middle turbinate middle meatus sphenoid sinus
superior meatus (frontal,
ethmoid maxillary sinus) middle meatus ostium
OMC ( 1) ostiomeatal unit OMC

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133
Middle
turbinate
Frontal
sinus
Orbit
Maxillary
sinus
Inferior
turbinate
1 ostiomeatal complex ()
OMC
(deviated nasal septum)
(septal spur) middle turbinate
air cell (concha bullosa)
maxillary sinus (uncinate process) OMC (displaced uncinate process)
13

14 OMC

(nasotracheal intubation) nasogastric tube

2
1. (structural cause) OMC
2559
134
2. (mucosal obstruction cause)

(inflammation/ infection)
1.

15

( )
(localized sinusitis)
8
maxillary sinusitis
16
visual analog scale (VAS)
mild, moderate severe mild VAS
1-3 moderate VAS

4-7 severe VAS
7 17

(quality of life)

(mild severity)
18
2.
inferior turbinate

(postnasal dripping to oropharynx) (rhinitis)
/ (nasopharyngitis)
middle meatus ( 2)
OMC
(nasal speculum) middle meatus inferior turbinate
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135
middle meatus topical

decongestant oxymetazoline ephedrine inferior turbinate
endoscope (otoscope ) OMC
UP
MT
S
C
2 () middle meatus (UP = uncinate process,
MT = middle turbinate, S = septum, C = choana)
OMC
(polyp)19 middle meatus
81-8720
maxillary sinus (antral aspiration)

3.
2.1 (plain sinus x-rays) 21

(immunocompromised host) ( 3)
2559
3 (Waters view) (air-fluid level) ( )

maxillary sinus
136
2.2 (CT scanning)

OMC

(unilateral
symptoms)

1.

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137
22
bronchial hyperresponsiveness22, 23
lysozyme lactoferrin
secretory IgA nitric oxide

22, 23
2. postnasal
drip aspiration
radioactive tracer maxillary sinus
pulmonary aspiration radioactive tracer24
3. Naso-sinobronchial reflex
5 parasympathetic
10
parasympathetic
(receptors) /

Corren 25 nasal provocation 30
bronchial hyperresponsiveness reflex
4.
( 4) eosinophils
nasal allergen challenge 24
airway resistance (mediators) IL-5
eosinophils eosinophils
airway
remodeling collagen subepithelium basement
membrane 26

27 50 70

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138
22,23

28 2
2
Nasal inflammation
Inflammatory cytokines
Adhesion molecule expression
Bone marrow activation
Endothelial cell activation
Circulating inflammatory
cells activation
Circulating
inflammatory cells
Bronchial inflammation
4
(systemic circulation)

10 reflex bronchospasm

eosinophils 29 Newman
30 eosinophilia
Bardin 24

radioactive tracer
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139

acetylsalicylic acid (ASA) triad (aspirin
intolerance)

corticosteroids
22, 23

(orbital complication) (intracranial complication)
(osseous complication)31
1.
1.1
1.1.1 (eustachian tube dysfunction)

1.1.2
(otitis media with effusion)

1.1.3
(acute otitis media)

1.2 (chronic pharyngitis)
1.3 (chronic laryngitis)
1.4 (chronic cough)
1.5 (chronic bronchitis)
1.6 (bronchial asthma)
2. (orbital complication)
ethmoid sinus ethmoid sinus

lamina papyracea 31
32
5 Chandlers classification33
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140
2.1 Periorbital cellulitis (preseptal edema)

periorbital cellulitis
orbital septum soft tissue

2.2 Orbital cellulitis orbital septum
(proptosis) (limitation of
ocular motion) orbital cellulitis
subperiosteal abscess 2
orbital cellulitis

subperiosteal abscess
48

2.3 Subperiosteal abscess
(ophthalmoplegia)
2.4 Orbital abscess
subperiosteal abscess
orbital abscess
aerobic anaerobic
central retinal artery occlusion optic neuritis corneal ulceration pan-ophthalmitis
2.5 Cavernous sinus thrombosis cavernous sinus
3, 4, 5 6
papilledema morbidity and mortality rate

3. (endocranial complication)

meningeal irritation
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141
neurological deficit frontal sinusitis ethmoid sinusitis

diploic veins (erosion) cerebritis
necrosis aerobic bacteria ( Streptococcus
Staphylococcus species) anaerobic bacteria
4. (osseous complication)
osteomyelitis frontal sinus
(Potts puffy tumor)
coma

1. (medical management of rhinosinusitis)

1.1 (eradicate infection)

Streptococcus pneumoniae, Haemophilus influenzae
Moraxella catarrhalis amoxicillin
82.3
68.734 14
Pseudomonas spp., CNS
gram negative bacteria
amoxicillin/clavulanic acid 2nd
3rd generation cephalosporin newer generation of macrolide ( clarithromycin)
quinolone ( levofloxacin) 3-4
1.2 (reduce
inflammatory process and promote ventilation and drainage)
(intranasal
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142
steroids)
35

36
(nasal septal perforation) (epistaxis)37

(systemic bioavailability) 405037
137

( 2 )
38
1.3
1.3.1. (decongestant)
pseudoephedrine, phenylephrine
ephedrine, phenylephrine, oxymetazoline
inferior turbinate 39
middle meatus
5 rhinitis medicamentosa

1.3.2.

40
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143
1.3.3. (0.9% normal saline solution)

41
(hypertonic saline)
42
1.4
steam inhalation, immunomodulator, furosemide, proton pump inhibitors,
antileukotrienes
1.5
(reduce predisposing factors)

2. (surgical management of rhinosinusitis)

OMC
2.1 (external approach)
maxillary sinus (CaldwellLuc operation) ethmoid sinus sphenoid sinus
(external ethmoidectomy-sphenoidectomy) frontal sinus
(transfacial frontoethmoidectomy: Lynch or Lothrop operation)

2559
144

/
2.2 (endonasal approach by nasal
endoscope)
endoscopic sinus surgery (ESS)
OMC
sharp
instruments (true cutting) shaver powered instruments navigator
OMC

Rachelefsky 43
48
80
67 21
Friedman 44
Oliveira 45

methacholine challenge

Weille46 500 72

100
56 10
Davison47
24 23 75 Mings 48 62

88 prednisolone
2559
145
(ESS)
English49 ESS ASA triad corticosteroids
205 40 corticosteroids
44 corticosteroids
Manning 50 ESS 14
corticosteroids 11
12 corticosteroids
11 13
Parsons Philips51 ESS
86 96
Nishioka 52
20 16-72 85
75
81

2559
146

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37. Salib RJ, Howarth PH. Safety and tolerability profiles of intranasal antihistamines and intranasal
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38. Benitez P, Alobid I, De Haro J, Berenguer J, Bernal-Sprekelsen M, Pujols L, et al. A short course of oral
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39. Stringer SP, Mancuso AA, Avino AJ. Effect of a topical vasoconstrictor on computed tomography of
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40. Bhattacharyya N. The economic burden and symptom manifestations of chronic rhinosinusitis. Am J
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41. Bachmann G, Hommel G, Michel OI. Effect of irrigation of the nose with isotonic salt solution on adult
patients with chronic paranasal sinus disease. Eur Arch Otorhinolaryngol. 2000;257(10):537-41.
42. Rabago D, Zgierska A, Mundt M, Barrett B, Bobula J, Mabrry R. Efficacy of daily hypertonic saline nasal
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43. Rachelefsky GS, Katz RM, Siegel SC. Chronic sinus disease with associated reactive airway disease in
children. Pediatrics. 1984;783:526-9.
44. Friedman R, Ackeman M, Wald E. Asthma and bacterial sinusitis in children. J Allergy Clin Immunol.
1984;74:185-9.
45. Oliveira CA, Sole D, Naspitz CK, Rachelefsky GS. Improvement of bronchial hyperresponsiveness in
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46. Weille F. Studies in asthma: nose and throat in 500 cases of asthma. N Engl J Med 1936;215:235-6.
47. Davison F. Chronic sinusitis and infectious asthma. Arch Otolaryngol. 1969;90:292-307.
48. Mings R, Friedman WH, Linford P, Slavin RG. Five-year follow-up of the effects of bilateral intranasal
sphenoethmoidectomy in patients with sinusitis and asthma. Am J Rhinol. 1988;2:13-16.
49. English GM. Nasal polypectomy and sinus surgery in patients with asthma and aspirin idiosyncrasy.
Laryngoscope. 1986;96:374-80.
50. Manning SC, Wasserman RL, Silver R, Phillips DL. Results of endoscopic sinus surgery in pediatric
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2559
2559
150
151

.. 2558

(physical) (psychological) (social)

1)
3
3 8
8
8 8 1-5
3

3
2559
152

2)

(chest x-ray) (alarming symptoms)

1)
1.1 Asthma
1.2 Cough variant asthma
1.3 Non-asthmatic eosinophilic bronchitis
2) Upper Airway Cough Syndrome (UACS)
2.1 Rhinitis
2.2 Sinusitis
2.3 Posterior nasal drip
3) Gastro-esophageal reflux disease (GERD)/laryngopharyngeal reflux (LPR)
4) angiotensin converting enzyme inhibitor (ACE-I)
5)
6) (chronic bronchitis)

3 8
(post-infectious cough)

GERD 2,3
1,5,6 .. 2540
2559
153
(chest x-ray) postnasal drip post-infectious cough 45

asthma 26 postnasal drip asthma 13 ACE-I 4
bronchiectasis 4 idiopathic 3 GERD 1.66

sinobronchial syndrome1
3)
3.1
3.1.1 (characteristics)
1)
2) (productive) (nonproductive)
3)
non-allergic inflammation

(bronchiectasis)
4) (diurnal variation)
5) aerosol

6)
10
gastroesophageal reflux lower esophageal sphincter tone
(heartburn) (regurgitation)
(extra-esophageal GERD)
severe allergic rhinitis
postnasal drip GERD
7) (throat clearing) postnasal drip syndrome
2559
154
8) (alarming symptoms)

3.1.2 angiotensin converting enzyme inhibitor (ACE-I)
3.1.3 (atopic diseases)
autoimmune diseases (interstitial lung diseases)
3.1.4

3.1.5
active passive smoker
active smoker

cough reflex
3.1.6 (upper respiratory tract infection)

8

3.1.7
(viral infection)
14 21
3 7
2559
155
3.1.8
(chronic silent aspiration)
3.2
3.2.1
inferior turbinate (nasal polyp) (postnasal drip posterior
pharynx) cobble stone posterior pharynx (glandular pharyngitis)
(cheilitis)
(allergic shiner) chronic
congestion lower eyelid venous plexus
80
3.2.2 wheeze, expiratory rhonchi
coarse crepitation bronchiectasis
3.3 (Investigations)
3.3.1 (Primary care)
3.3.1.1 (Chest X-ray) 1-5,7
(Level of evidence 1, Grade of
recommendation ++)
3.3.1.2 (plain x-ray of paranasal sinus)
/ 8,9
(Level of evidence 4, Grade of recommendation +)
ethmoid sinus 10
maxillary sinus
11
3.3.1.3
2559
156
1. (spirometry) 2 (airway
obstruction)3 (Level of evidence 2, Grade of recommendation ++) []
2. peak expiratory flow rate (PEFR)
forced expiratory volume
1 (FEV1) 12 (Level of evidence 2, Grade of recommendation
+/-) serial PEFR
(Level of evidence 4, Grade of recommendation +/-) [ ..
2550]
3.3.2 (Secondary care)
3.3.2.1 Bronchoprovocative test (airway hyperresponsiveness, AHR)

asthma 2,13
methacholine challenge test methacholine challenge test
14 (Level of evidence 2,
Grade of recommendation +)
3.3.2.2 (High-resolution computed tomography, HRCT)
(bronchiectasis), interstitial lung diseases
(bronchiolitis) 3 (Level of evidence 3, Grade of recommendation+)
3.3.2.3 Indirect laryngoscopy laryngopharyngeal reflux
(ENT)3 (Level of evidence 1, Grade of recommendation ++)
3.3.2.4 (computerized tomography paranasal sinus)
9 (Level of evidence 2, Grade of recommendation -)

4 (Level of evidence 3, Grade of
recommendation ++)
2559
157
3.3.2.5
1) 24-h esophageal pH monitoring
2) Esophageal manometry/impedance testing
(Level of evidence 2, Grade of recommendation +/-)
3.3.2.6 (sputum eosinophil)
(fractional exhaled nitric oxide,
FeNO) FeNO eosinophilic inflammation FeNO
asthma, cough variant asthma non-asthmatic eosinophilic bronchitis15
16
(Level
of evidence 2, Grade of recommendation +)
3.3.2.7 specific IgE skin prick test aeroallergen
4 (Level of evidence 2, Grade of recommendation ++)
4)

1. C-fibers (nociceptor cough) mucosa
(inflammatory mediators) (irritants)
2. Cough receptors (mechanoreceptor cough) epithelium larynx, trachea
mainstem bronchus (punctuate mechanical)

nucleus tractus solitarius (nTS)

brainstem reflex cough
cortex urge to cough behavioral cough
2559
158

cough reflex
(inflammation)

5)
5.1) subjective cough severity score, cough diary

Leicester validation
3 (physical)
(psychological) (social)
minimal clinical importance difference
17 Leicester
18
5.2) objective

6)

ACE inhibitor, UACS, cough variant asthma
GERD
ACE-I
UACS (antihistamine) / decongestant (Level of evidence
3, Grade of recommendation +) /
decongestant 7
moderate-to-severe allergic rhinitis
2559
159
(Level of evidence 1, Grade of recommendation ++)

2
(beta-2 agonist
bronchodilator) / (inhaled corticosteroid ICS) /
2
methacholine (non-asthmatic
eosinophilic bronchitis) /
2 (steroidresponsive cough) (Level of evidence 3, Grade of recommendation +)
2-4
methacholine

(GERD)
UACS
4 8

7)

7.1 ACE inhibitor induced cough
10 30

1-4 19 (Level of evidence 3,
Grade of recommendation +)
7.2 Cough variant asthma
2559
160

20

13
1. (intermittent) 2- agonist
(relievers) 2-4
2. (persistent) 1
(controllers)
(inhaled corticosteroid ICS)13 (Level of evidence 1, Grade of
recommendation ++)

(leukotriene receptor antagonist, LTRA)21 (Level of
evidence 1, Grade of recommendation ++)
ICS classic asthma wheezing
LTRA22 (long-acting 2 agonist,
LABA) (ICS/LABA)23 24 (Level of evidence 1,
Grade of recommendation ++)
4

7.3 Upper airway cough syndrome
rhinitis, sinusitis postnasal drip
2559
161
7.3.1 (sinusitis)
()
(rhinitis) rhinosinusitis
(acute rhinosinusitis)
(chronic rhinosinusitis, CRS) 12 12

(CRS with nasal polyp)
(CRS without nasal polyp)
/
(united airway inflammation)

1.
(anterior rhinorrhea) (postnasal drip) 12
2. otoscope

(Plain film paranasal sinus)
25

1.1 26 2
1.1.1 (first-line antibiotics) amoxicillin

penicillin macrolides clarithromycin azithromycin
1.1.2 (second-line antibiotics)
1) Beta-lactam/ beta-lactamase inhibitor amoxicillin/clavulanate
2559
162
2) Second third generation cephalosporin cefuroxime, cefpodoxime proxetil

cefdinir
3) Respiratory fluoroquinolones levofloxacin moxifloxacin
1.2 27
1.2.1 (nasal steroid)
1.2.2 (promoting drainage from paranasal
sinuses) (Level of evidence 3, Grade of recommendation +)
1.2.3 decongestant
(Level of evidence 3, Grade of recommendation +)
1.2.4 /
1 chlorpheniramine
empiric
4
(nasal telescopy)
(middle meatus)
7.3.2 (Rhinitis)
(rhinitis)
allergic rhinitis (AR) non-allergic rhinitis (NAR)
vasomotor rhinitis, drug-induced, hormonal-induced,
environment/irritant-induced, gustatory reflex
(non-allergic rhinitis with eosinophilia syndrome, NARES)
1 3 1) (sneezing) 2)
(rhinorrhea) 3) (congestion) 1 3
2559
163
(unrecognized form) (throat clearing),

(mouth breathing), (headache),
eustatian tube dysfunction,

AR NAR28 capsaicin cough

sensitivity 29

1.

(Level of evidence 1, Grade of recommendation ++)
(Level of
evidence 1, Grade of recommendation ++)
(Level of evidence 3, Grade of recommendation +) (Leukotriene receptor
antagonist, LTRA)
(Level of evidence 2 , Grade of recommendation -)
30 (Level of evidence 2 , Grade of recommendation ++)

4 (
.. 2554)
2. postnasal drip
1 dexbrompheniramine / pseudoephedrine
3 ipratropium
31-33
2559
164
7.4 Nonasthmatic eosinophilic bronchitis

60 rhinitis allergic rhinitis 10
peripheral eosinophilia 20 specific IgE antibodies 34
12
methacholine serial peak flow diurnal
variation cough variant asthma
fractional exhaled
nitric oxide (FeNO) eosinophilic bronchitis asthma cough variant
asthma15
Nonasthmatic eosinophilic bronchitis
(budesonide 800 mcg ) (Level of
evidence 4, Grade of recommendation ++) 2-4 35

2 (Level of evidence 4, Grade of recommendation +)
7.5 (Cough related reflux disease)
(gastric
content)

36

2559
165
1) (esophageal symptoms) 2
(heartburn) (regurgitation)
(chest pain)
4
(erosive esophagitis) (esophageal stricture)
Barettes esophagus (esophageal cancer) adenocarcinoma
2) (extraesophageal symptoms)

(laryngopharyngeal reflux LPR)

36,37

(laryngopharyngeal reflux LPR)

1) Esophagopharyngeal reflux (microaspiration theory)38

2) Laryngeal chemoreflex (reflex pathway afferent limb stimulated superior
laryngeal nerve efferent limb recurrent laryngeal nerve)
3) Vagally mediated reflex ( sensory stimulation distal esophagus laryngeal
stimulation laryngospasm afferent limb of vagus nerve)
4) (Increased cough reflex)
5)
39-42
2559
166

43-75
43,44 10

45


1.
2. ACE-I
3.
4.

methacholine
5.
6. nonasthmatic eosinophilic bronchitis
eosinophil
inhaled systemic corticosteroids

1-6
45
proton pump inhibitor

2559
167
1. (Esophagogastroduodenoscopy)
(erosive esophagitis)
Barretts esophagus

55
16 47
2. - 24
(gold standard)

60-10048
6649

(symptom association)
3. Multichannel intraluminal impedance pH monitoring

proton pump inhibitor
histamine receptor 2 antagonist proton
pump inhibitor typical esophageal GERD
omeprazole 20 mg 1 proton pump inhibitor
4-8 (Level of evidence 2, Grade of recommendation ++)
4 8

(open-label trial)50
proton pump inhibitors (
) ( 2 ) 47 9
2559
168
(odds ratio, OR 0.46; 95% CI

0.19-1.15)42 2 51,52

49 proton pump inhibitor
4-8 proton
pump inhibitor47
7.6 Post-infectious cough

(upper respiratory tract infection, URI)
URI 2 Mycoplasma,
Chlamydia Moraxella catarrhalis
8 8
2 10 25 25 50
Mycoplasma Bordetella pertussis cough
hypersensitivity airway inflammation airway sensory nerves
cholinergic motor pathway bronchoconstriction airway hyperresponsiveness 53
cough hypersensitivity Bordetella pertussis
Pertussis
2
inspiratory whoop ( ) polymerase chain reaction
nasopharynx (sensitivity 80-100%) (Level of evidence 3, Grade of recommendation +/-)
culture (sensitivity 25-50%) (Level of evidence 3, Grade of recommendation +)
serology (pertussis IgG, IgA titer) 2 2 3-4
(sensitivity 60%)54 (Level of evidence 3, Grade of recommendation +/-)
Post-infectious cough
2559
169
pertussis
8
55,56 (Level of evidence 4, Grade of recommendation +),
inhaled ipratropium57 (Level of evidence 2, Grade of recommendation +)
(prednisolone 30-40 mg )
1-2 3 (Level of evidence 3,
Grade of recommendation +/-) (Level of evidence 4,
Grade of recommendation +) montelukast58 (Level of evidence 1,
Grade of recommendation -)

postnasal drip

pertussis
macrolide erythromycin trimethoprim/sulfamethoxazole
2 53,54 isolation 5 (Level of evidence 1,
Grade of recommendation ++)
pertussis immunoglobulin2 (Level of evidence 1, Grade of recommendation -)
Sinobronchial syndrome

sinobronchial syndrome
chronic cough guidelines 1
mucoid mucopurulent
(chronic sinusitis) (chronic
lower airway inflammation) diffuse bronchiectasis diffuse panbronchiolitis (DBP)
chronic bronchitis
2559
170
postnasal drip, nasal discharge throat clearing

upper respiratory tract infection post nasal drip cobble
stone appearance oropharynx pneumococcus H. influenzae
serum IgA cold agglutinins
(computed tomography)
Sinobronchial syndrome
expectorant 14-membered
ring macrolides erythromycin 300-600 mg clarithromycin 250-500 mg
roxithromycin 150-300 mg 2-12 1 (Level of evidence 3, Grade of
recommendation +)

(Quality of evidence)
1

1.1 (systematic review) (randomized
controlled clinical trials)
1.2
1
2

2.1 (non-randomized controlled clinical
trials)
2.2

2559
171
2.3 (cohort, case-control)

/
2.4 (multiple time series)
2.5
3

3.1 (descriptive studies)
3.2

4
4.1 (consensus)

4.2 2

(Strength of recommendation)
++

(cost effective)
+

+/-
2559
172
(airway obstruction)
1) 2)
(reversibility) /
(variable airflow limitation)
FEV1/FVC 0.75-0.8 60
FEV1 200 ml 12
20 / controller 4
(variable airflow obstruction)

peak expiratory flow rate (PEFR)
peak expiratory flow rate (PEFR)
PEFR 60 L/min 20
PEFR PEFR
2559
173
PEFR 1-2
( 10 PEFR 2
PEFR 20
4
PEFR (peal flow variability, PFV)
PFV (%) = (PEFR PEFR ) PEFR (PEFR
+ PEFR /2) 100%
(Bronchoprovocative test)
histamine methacholine

FEV1 20 methacholine
methacholine FEV1 20
(PC20) 8 mg/dl PC20 1 mg/dl
(severe AHR) PC20 16 mg/dl
methacholine challenge test positive predictive value 78-88

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179
(Acute asthma management: Whats new in 2015-16)

250,000
3 4 100,0001

Global strategy for asthma management and prevention (GINA
guideline) National Asthma Education and Prevention program (NAEPP guideline)

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2
peak expiratory flow (PEF) Forced expiratory
volume in one second (FEV1)

3
PEF

1.

(high risk of asthma-related

death)4 1
-
- 1
-
-
- (short-acting inhaled B2 agonist; SABA)
1
-
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- asthma action plan

2.

(cyanosis)

GINA 25584 PEF

1 6 GINA
25584

( )

( )

Peak Expiratory Flow(PEF)
100 120
90 95
50 predicted
personal base value
2559

30
120
90
50
182
2 5 5
GINA 25584
()
95
100
Central cyanosis

92
200 0 3
180 4 5

(rapid reversal airway obstruction) systemic steroid

GINA

- 20 3
- 92
93 95 94 98
- systemic steroid

- 92
- ipratoprium bromide 20 3
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- systemic steroid
- 30 45
-
anticholinergic systemic steroid magnesium sulfate

1. Inhaled short-acting Beta2 agonist
nebulizer MDI with spacer
nebulizer passive
90 continuous intermittent
nebulizer 5, 6
continuous Salbutamol
0.15mg/kg/dose NSS 2.5 4 ml oxygen flow 6 8 L/min
salbutamol MDI 2 4 puff/ 20 30
10 puff/
2. Inhaled ipratropium bromide
anticholinergic inhaled Beta2 agonist

7, 8
Ipratropium bromide 20 kg 250 mcg/dose
20 kg 500 mcg/dose
3. Systemic corticosteroid

4 systemic steroids 1

9-11

Beta2 agonist
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Prednisolone 1-2 mg/kg/day 60mg/day Hydrocortisone 5 mg/kg/dose
6 250 mg/ Methyl prednisolone 1 mg/kg/dose
6 60mg/dose
3 5 7

HPA axis12, 13
4. Magnesium sulphate
Magnesium sulphate

FEV1 25 30
14 50% Magnesium sulphate
25 75 mg/kg 2 g 30
magnesium sulphate
magnesium sulphate
magnesium sulphate
magnesium sulphate
15, 16

5. Aminophylline/theophylline
2-agonist
17
6. Noninvasive ventilation
non-invasive ventilation (NIV)
NIV
18
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Helium, Leukotriene modifier,

epinephrine/adrenaline, sedative agent
Long Acting Beta 2 Agonist (LABA)
Formoterol

(monitoring)

20 30
PEFR FEV1
60 PEF
70 90

(pneumothorax)
Arterial blood gas pulse
oximetry PEF 30 50

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-
-
- NIV persistent hypercarbia ( PaCO2 50 mmHg)
hypoxemia
- FiO2 60
- hypercarbia PaCO2

bronchial hyper-responsiveness

Rapid Sequence Intubation (RSI)
RSI
(induction)
Ketamine

PaCO219, 20

PEF 60 predicted

- 60

- 95
peak expiratory flow 60 80 predicted personal base value
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187

- 3 5
2 5
10
- Salbutamol MDI 4
3
- 7

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190
191
(Asthma prevention in children: is it possible?)

(asthma)

1, 2

3
(primary prevention)

(genetic
susceptibilities) (environmental exposure)
(immune dysregulation) 3
4

1.

2.

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192
3. (risk factors)

4. Biomarkers

5.

(Host factors)
1. genetic polymorphisms 17q21
ORMDL3, GSDMB, ZPBP2, IL1RL1/IL18, TSLP, HLADQ, IL2RB, IL33
SMAD35, 6
2.
7
3.
8
4. - 9

5. 10
(Environmental factors)
1. Aeroallergen sensitization sensitization

1-2 11, 12
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193
sensitization specific IgE

12, 13
2. respiratory syncytial virus (RSV)
rhinovirus (RV) 14-16
RV 6 10 allergic
sensitization 15, 17
3.

18 1
19, 20
4.

21
5. ozone, sulfur dioxide, particulate matter nitrogen oxide
22
6. (the gut microbiome)
/ gut microbiome
4
7. (immunoregulatory)
23 alveolarization surfactant 24
wheezing 25
8. (antioxidants)

26
9.

27
2559
194

(single intervention)
(multifaceted intervention)

1. RSV
RSV RSV immunoprophylaxis (Palivizumab)
429 recurrent wheezing
1 Palivizumab
Palivizumab
RSV (the RSV fusion (F)
glycoprotein)
28
RSV
RSV Ribavirin
RSV
Chen
CH 2 RSV bronchiolitis
Ribavirin 44 6 Ribavirin
Ribavirin recurrent wheezing allergen
sensitization Ribavirin 29
Ribavirin RV

2559
195
2. immunomodulation
2.1 (Probiotics)

microflora
Th1 Th2 microflora

30, 31 32 33
34
Bifidobacterium species (B. bifidum, B.
longum, B. breve B. lactis), Lactobacillus species (L. acidophilus, L. casei, L. lactis, L.
reuteri, L. paracasei L. rhamnosus)
1
25 ( 6 ) 108-1011 colony
forming units meta-analysis 9
3,257
( 11.2
10.2 )35
2.2 (Prebiotics)

bifidobacteria lactobacilli
galacto- fructo-oligosaccharide ( GOS/FOS 9:1) (8 g/L)
36
2.3 (Immunostimulants)
synthetic thymic extracts
OM-85 BV Broncho-Vaxom 8
OM-85 BV
2559
196
3 6 wheezing
OM-85 BV37, 38
2.4

endotoxin,
muramic acid -glucans 39-41

2-3 42
25 (the protective farm-effect)43

19
20
19
3. allergen sensitization allergic inflammation
allergic sensitization

(allergen avoidance)
(dietary intervention) (single intervention) (multifaceted intervention)
multi-faceted intervention regimen single intervention
44-46
microbiome
allergic
sensitization
allergic sensitization subcutaneous immunotherapy (SCIT) SCIT
allergic sensitization
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197
47 (allergic
rhinitis, AR) Jacobsen L (the PAT study)
AR 6-14 205 SCIT (birch / grass pollen) 3
7 SCIT
SIT odds ratio
4.6 SCIT
AR

biomarkers

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Chronic Eosinophilic Pneumonia

eosinophils chronic obstructive pulmonary
disease eosinophilic inflammation corticosteroid
corticosteroid responsiveness eosinophilic inflammation
eosinophilic lung diseases pulmonary eosinophilic
syndrome eosinophils
chronic
eosinophilic pneumonia (CEP) CEP

1, 2
Eosinophilic lung diseases (Classification of eosinophilic lung diseases)

eosinophilic lung diseases 3
1) Primary eosinophilic lung diseases
- Idiopathic eosinophilic pneumonias eosinophilic pneumonia
- Churg-Strauss vasculitis
- Idiopathic hypereosinophilic syndrome
- Allergic bronchopulmonary aspergillosis (ABPA)
- Bronchocentric granulomatosis
2) Secondary eosinophilic lung diseases
- Drug-induced pulmonary eosinophilia
- Parasite-induced pulmonary eosinophilia
- Fungal-induced pulmonary eosinophilia
3) Diseases occasionally associated with eosinophilia
- Idiopathic pulmonary fibrosis
- Sarcoidosis
- Hypersensitivity pneumonitis
- Malignancy
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- Langerhans cell granulomatosis

- Cryptogenic organizing pneumonia
pulmonary infiltrate with eosinophilia 3
1) Simple pulmonary eosinophilia
2) Acute eosinophilic pneumonia
3) Chronic eosinophilic pneumonia

1
1 Simple pulmonary eosinophilia, acute eosinophilic pneumonia chronic
eosinophilic pneumonia
Features
Acute Eosinophilic
Pneumonia
Idiopathic, tobacco smoke,
drugs
15 days
Chronic Eosinophilic
Pneumonia
Idiopathic
Duration of symptoms
Simple Pulmonary
Eosinophilia
Idiopathic, drugs,
parasites
12 weeks
Respiratory failure
Blood eosinophils
BAL findings
Never
Increased
Eosinophils
Very rare
Increased
Eosinophils
Chest x-rays
Transient lung
infiltrates
Rare
Unnecessary
Rare
Frequent
Normal
Eosinophils, lymphocytes,
and neutrophils
Diffuse lung infiltrates,
Kerley B lines
Frequent
Corticosteroid (212 weeks)
Rare
Etiology
Pleural effusions
Treatment
Clinical relapse
Several weeks to months
Peripheral lung infiltrates

Rare
Corticosteroid (several years)
Frequent
Chronic eosinophilic pneumonia (CEP)

eosinophils alveolar spaces interstitium
3 (rare disorders) Icelandic
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203
registry 0.23 100,000 4 30 40

2 15-8 50 (asthma)
atopic disease 6, 9 2

subacute chronic onset 1
CEP
1. (productive cough)
2. (fever)
3. (breathlessness)
4. (weight loss)
5. (night sweat)
6. 5
(respiratory failure)
(mechanical ventilator)10, 11
(tachypnea), crackles, wheezing 356
CEP

(laboratory)
1. (chest imaging) alveolar infiltration unilateral
bilateral alveolar infiltration infiltration peripheral lung zone sub-pleural area
segment (non-segmental distribution)
photonegative of pulmonary edema upper lobes6
alveolar infiltration ground glass opacity ( chest X-ray)
consolidation ground glass opacity consolidation 12
cryptogenic organizing pneumonia13, sarcoidosis14 drug induced
pneumonitis14 (chest imaging)
migratory infiltration bronchiectasis mediastinal lymphadenopathy
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204
6, 15 pleural effusion 105, 6, 12, 16, 17 pleural effusion

massive pleural effusion 17
2. Complete blood count eosinophil (eosinophilia)
eosinophil 500 cell/mm3 eosinophil 1000
cell/mm36, 18 eosinophilia 5, 16, 19 eosinophilia
eosinophil count bronchoalveolar lavage (BAL) 4018
thrombocytosis 20-22
3. Pulmonary function test restrictive pattern
obstructive pattern obstructive pattern diffusion
lung capacity for carbon monoxide 6
4. Bronchoscopy CEP
bronchoalveolar lavage (BAL) cell count eosinophil
(eosinophilia) eosinophil 25 eosinophil
BAL
12 956 CEP
eosinophilia BAL histopathology23
neutrophils, lymphocytes, mast cells
lymphocytes eosinophils6, 18 transbronchial biopsy
eosinophils infiltrate specimen
histopathology chronic eosinophilic pneumonia24 open
lung biopsy
5. investigation erythrocyte sedimentation rate (ESR), Creactive protein(CRP), serum total immunoglobulin E (IgE)6 rheumatoid factors
8, 25
Histopathology3, 18, 26
histopathology CEP eosinophil alveoli septa,
alveolar lumen, interstitium eosinophils pulmonary vessels granulomatous
vasculitis necrotizing vasculitis7 eosinophilic abscess5, 26 interstitial
edema fibrosis foci of organizing pneumonia 5, 7
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205
CEP 2
computed tomography high resolution computed
tomography photonegative of pulmonary edema
blood eosinophilia 1000 cell/mm3
bronchoalveolar lavage (BAL) eosinophils 25 27
eosinophilic lung disease
histopathology BAL eosinophils
typical CEP systemic corticosteroid
histopathology
chronic eosinophilic pneumonia (CEP)

1. Cryptogenic organizing pneumonia (COP)
subacute chronic process
peripheral infiltration migratory pneumonia 13, 28, 29 chronic eosinophilic
pneumonia COP systemic corticosteroid30 COP
blood eosinophilia bronchoalveolar lavage eosinophilia
2. Acute eosinophilic pneumonia (AEP) AEP CEP
1 14 31, 32
AEP (asthma) atopic disease 30
CEP
31, 32 AEP pleuritic chest pain
CEP AEP diffuse bilateral airspace
interstitial opacities peripheral predominance pleural effusion
pleural effusion
complete blood count blood

eosinophilia18, 31 bronchoalveolar lavage (BAL) eosinophil
4018, 31
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3. Churg-Strauss syndrome eosinophilic granulomatosis with polyangiitis

systemic eosinophilic vasculitis atopic disease
(allergic rhinitis), (asthma) 33 blood eosinophilia 10,000
cells/mm3 eosinophils systemic vasculitis34

18 sinusitis,
rhinitis, nasal polyps, neurological system (mononeuritis multiplex, central nervous system),
gastrointestinal system (diarrhea, abdominal pain, gastrointestinal bleeding, gastro intestinal
perforation), cardiovascular system (congestive heart failure, acute coronary syndrome,
pericarditis, hypertension),pulmonary infiltration, skin rash (purpura, urticaria, nodules), renal
insufficiency, arthralgia, myalgias, fever, mild lymphadenopathy 35 reversible
exopthalmos hearing loss36
(chest imaging) Churg-Strauss syndrome
chronic eosinophilic syndrome transient patchy infiltration, patchy infiltration
symmetrical infiltration lobe
segment infiltration radiating from hilum, subpleural
distribution diffuse interstitial infiltration, noncavitating nodular
infiltration , centrilobular nodules pleural effusion ( exudative
pleural effusion eosinophil 37) mediastinal nodes 37-43
blood eosinophila, erythrocyte sedimentation rate (ESR)
total immunoglobulin E (IgE) 34, 36 50 Antineutrophil cytoplasmic autoantibodies (ANCA) perinuclear pattern (p-ANCA) antimyeloperoxydase 44 bronchoalveolar lavage eosinophils
Gold standard Churg-strauss syndrome histopathology
open lung biopsy necrotizing vasculitis
small arteries , capillaries veins
eosiniphils, multinucleated giant cells, neutrophils / epithelioid cells granuloma
interstitium perivascular allergic granuloma eosinophil alveolar
interstium capillaritis3, 43, 45-47
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207
CEP Churg-Strauss vasculitis ChurgStrauss vasculitis

opacities p-ANCA
bronchoalveolar lavage
histopathology

histopathology
CEP spectrum Churg-Strauss syndrome18, 27, 48

4. Allergic broncho-pulmonary aspergillosis (ABPA) allergic broncho-pulmonary
mycosis hypersensitivity syndrome type 1 type 3 Aspergillus
fumigatus 18, 49 (asthma), blood esosinophilia, total
immunoglobulin E (IgE) 1000 IU/L
migratory pulmonary infiltration, bronchiectasis central bronchiectasis,
high attenuation mucous plugging bronchiectasis finger in glove
appearance bronchiectasis high attenuation mucous plugging
bronchiectasis CEP hypersensitivity fungus skin prick test
specific IgG or IgE to Aspergillus50
5. Drug-induced eosinophilic pneumonia eosinophilic pneumonia
nonsteroidal anti-inflammatory drugs(NSAIDS), cocaine, nitrofurantoin, minocycline,
sulfonamides, ampicillin, daptomycin51, diphenylhydantoin, and methotrexate 52
www.pneumotox.com
6. Helminth infection
Ascaris lumbricoides, hookworms (Ancylostoma duodenale, Necator
americanus) Strongyloides stercoralis Loeffler syndrome life cycles
transient pulmonary opacities transient blood eosinophilia
(nonproductive cough), (burning
sensation) wheezing
migratory opacities nodules , reticulonodular infiltration
consolidation3, 53 creeping
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eruption life cycle

Paragonimus westernmani, Echinococcus sp., Taenia solium54, Schistosoma sp., Trichinella
spiralis, Wuchereria bancrofti, Toxocara sp. , antibody

open lung biopsy3, 52, 53
7. Hypereosinophilic syndrome blood eosinophilia
1500 cells/mm3 6
eosinophil55 , , 56, 57 3040 70 7 3, 58
, , , (pruritus), ,
blood eosinophilia eosinophils 30-70
10,000 cells/mm3 eosinophilic metamyelocytes
eosinophilic myelocytes eosinophils (bone marrow)
endocardial fibrosis, restrictive cardiomyopathy, thrombus
thromboembolism artery vein Splinter
hemorrhages, renal infarcts, splenic infarcts, retinal arteriolar embolism, deep venous thrombosis,
femoral artery embolism, cerebrovascular accident diffuse small vessel cerebrovascular
occlusions peripheral neuropathy, mononeuritis multiplex,
encephalopathy gastrointestinal tract eosinophilic gastritis, eosinophilic
enterocolitis, eosinophilic colitis interstitial infiltration focal infiltration
peripheral area histopathology eosinophilic
infiltration lung parenchyma pulmonary arteries
bronchoalveolar lavage eosinophils
fibrosis arthralgia, arthritis, keratoconjunctivitis, retinal vessels abnormality 3,
55, 56

chronic eosinophilic pneumonia (CEP) hypereosinophilic syndrome
(Treatment)3, 18, 59
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CEP 10 7
CEP
randomized controlled trial high methodology studies
case series prednisolone CEP 0.5-1 mg/kg/day 2
4-6
6-12
intravenous high dose methyprednisolone 250 mg every 6 hours

corticosteroid 24-48
16 chest X-ray 14
1
5, 59 computed tomography chest X-ray60
eosinophils pulmonary function test forced vital
capacity (FVC), total lung capacity (TLC), diffusion capacity of carbon monoxide (DLCO) pulse
oxygen saturation (SpO2) fixed obstructive pattern
bronchoalveolar lavage

(relapse) 6
3, 5, 6 prednisolone
prednisolone 0.5 mg/kg/day 1-2

5-15 mg/day (alternate
day) 6-12 prednisolone relapse
prednisolone 3, 8
corticosteroid
1. Inhaled corticosteroid inhaled corticosteroid
(beclomethasone 1500-1600 mcg/day) oral corticosteroid
oral corticosteroid8, 61, 62
inhaled corticosteroid 63
inhaled corticosteroid
oral corticocorticoid
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2. Omalizumab omalizumab
(asthma) skin test specific allergen
oral corticocorticoid 64-66
Chronic eosinophilic pneumonia (asthma) atopic

disease 30-40
peripheral infiltration photonegative of
pulmonary edema blood eosinophilia bronchoalveolar lavage eosinophils
25

histopathology open lung biopsy systemic corticosteroid
6-12 systemic corticosteroid
(relapse)

1.
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6.
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difficult severe asthma

Difficult asthma
difficult asthma severe asthma difficult to
controlled asthma difficult asthma Global Initiative for Asthma (GINA) guideline
(current symptom control)
(future risk reduction) severity 1
ATS/ERS Taskforce For Asthma Control and Exacerbation 2009 asthma
control current clinical control future risk 2
severe asthma uncontrolled asthma

(healthcare
providers) (disease activity) (patients)

severe asthma asthma high intensity treatment
asthma high intensity treatment asthma
high intensity treatment treatment resistant asthma
refractory asthma

smoking allergen exposure refractory asthma (intrinsic
disease activity) corticosteroid insensitivity 3 difficult
asthma
British Thoracic Society 2009 difficult asthma asthma
BTS treatment step 4 5
inhaled corticosteroid (ICS) beclomethasone 800 mcg
long acting 2 agonist controller 4
National Institute for Health and Care Excellence (NICE)5 difficult
asthma high intensity treatments BTS step 4 5
acute severe asthma
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invasive ventilation, maintenace oral corticosteroid prednisolone

7.5 mg/ 6 2 1 fixed airflow
obstruction post bronchodilator FEV1 < 70% predicted
American Thoracic Society 2000 refractory asthma Preceding of ATS
workshop on refractory asthma major minor criteria refractory
asthma 1 2 major criteria 2 minor criteria
1) Major criteria asthma oral
corticosteroid 50% high dose inhaled corticosteroid
budesonide 1200 mcg
2) Minor criteria
- Asthma add on controllers LABA, leukotriene receptor
antagonist theophylline ICS
- short acting bronchodilator
- short course oral corticosteroid 3
- FEV1 80% diurnal variation peak
expiratory flow rate (PEFR) 20%
- inhaled corticosteroid 25%

- asthma exacerbation near fatal asthma6
(WHO) 2010 severe asthma severe asthma
3 (subgroups)7
1) Untreated severe asthma

2) Difficult to treat asthma

3) Treatment resistant asthma

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Innovative Medicine Initiative (IMI) 2010 problematic asthma

2 difficult asthma severe refractory asthma difficult asthma ( )
severe refractory asthma
asthma 8
Asthma severity ( ) asthma
control

(
) 2
1 severe asthma asthma potentially

treatment responsiveness co-morbidities difficult to control asthma (difficult asthma)
treatment resistance (refractory asthma)
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2 asthma control asthma severity
American Thoracic Society European Respiratory Society 20139 severe

asthma
6 International ERS/ATS guidelines on definition, evaluation
and treatment of severe asthma severe asthma asthma GINA
step 4-5 high dose inhaled corticosteroid (ICS) long acting beta agonist ICS
leukotriene modifier theophylline systemic corticosteroid
50%
uncontrolled asthma uncontrolled asthma
ATS/ERS guideline 2013
uncontrolled asthma asthma
1) Poor symptom control: Asthma Control Questionnaire (ACQ) > 1.5, Asthma
Controlled Test Score < 20, Not well controlled National Asthma
Education and Prevention Program GINA
2) Frequent severe exacerbation: systemic corticosteroid ( 3 )
2

3) Serious exacerbations:

4) Airflow limitation: (
) FEV1 < 80% predicted FEV1/FVC lower limit
normal
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severe asthma ATS/ERS 2013 guideline asthma

high dose ICS systemic corticosteroid biologic agents
asthma
high dose ICS
6-12
12 beclomethasone diproprionate (DPI CFC
MDI) 1000 mg/ HFA MDI 500 mg/, budesonide (DPI MDI) 800 mg/,
fluticasone proprionate (DPI MDI) 500 mg/ mometasone fuorate (DPI ) 800 mg/
high dose inhaled corticosteroid
severe asthma ATS/ERS 3

1) (severe or uncontrolled symptoms)
2) (persistent low lung function)
3) (frequent and serious asthma exacerbation)
Wenzel SE 2012 phenotypes severe
uncontrolled asthma10
difficult asthma subset severe asthma

treatment resistant asthma
(novel therapies) severe refractory
asthma
(5-10%) severe refractory asthma

Difficult asthma
difficult asthma
asthma (non-adherence)
inhaler (poor device technique)
(co-morbidities) difficult asthma
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3 severe asthma phenotypes Wenzel SE (

10)
1)
difficult asthma
(wrong diagnosis) asthma asthma
asthma asthma
mimickers 2
1.1 asthma chronic obstructive pulmonary
disease (COPD) allergic bronchopulmoanry aspergillosis (ABPA) vocal cord dysfunction
(VCD) Churg Strauss Syndrome (CSS)
1.2 asthma asthma vocal
cord dysfunction, congestive heart failure neuromuscular diseases endobronchial lesion
foreign body aspiration tumor
asthma clinical diagnosis heterogeneity

asthma

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4 asthma (asthma mimickers)

asthma (alternative diagnosis) ERS
monograph 12
asthma asthma elevated
serum IgE mucus plug allergic bronchopulonary aspergillosis (ABPA)
asthma Churg Struass Syndrome (CSS) systemic vasculitis
American College of Rheumatology asthma
blood eosinophilia paranasal abnormalities asthma
granulomatous vasculitis peri-vascular inflammation
(symptoms increase probability of asthma)
(symptoms decrease probability of asthma)
(isolated cough)
(excessive sputum production) (chest pain)
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(noisy breathing)
(alternative diagnosis) 1
5 (alternative diagnosis)
6-11 11 40 40 GINA 2014

1
asthma alternative diagnosis

2) (Patient adherence and inhaler
technique)
treatment compliance
treatment adherence severe asthma 50%11
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2
2.1 (poor compliance or non-adherence to
treatment)

2
(intentional
non-adherence)
(unintentional non-adherence)
12
-

inhaled
corticosteroid

-
(poor perception)
inhaler devices 1

inhaled corticosteroid
(impaired cognitive
function)
Treatmet adherence
70-100% (prescription)
adherence prescription subjective objective
methods
subjective methods (physician report)
(patients self report) (diary)
(questionnaire)
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objective methods personal digital VDO record

oral corticosteroid
plasma cortisol inahled corticosteroid urine cortisol
urine creatinine12
6 Smart-inhaler inhaler devices

software 13

(pharmacy dispensing) (inhaler) dose counter inhaler
(inhaler actuation) Smart-inhaler
(Nexus-6 Company, Auckland NZ)
pMDI inhaled corticosteroid ICS-LABA combination
canister websase software
Smart-inhaler devices turbuhaler soft-mist inhaler 13
treatment adherence 14
prescription refill
difficult asthma
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1 3 50%
15
(Strategies increase treatment adherence)
12
1) Pragmatic interventions audiovisual asthma
short message service (SMS)

(asthma education)
adherence
2) Tailor intervention

(goal) (preference)
asthma action plan
3) Pharmacy based intervention

prescription refill

2.2 (Correct inhaler technique)

inhaler devices (limitations)
(asthma in older adults)16
1) (peak inspiratory flow rate)
2) (manual
dexterity and co-ordination)
3) (cognitive
impairment)
GINA inhaler devices treatment
adherence assess adjust treatment
review of response asthma1
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7 inhaler techniques asthma

=
inhaler = inhaler ? = inhaler (
16)
(Optimal peak inspiratory flow rate)
DPI
(peak inspiratory flow rate)

1) (Inhaler device tester) testers
(auditory cues) qualitative assessment
2) peak inspiratory flow rate (PIFR)
(inhaler devices) inhalers
quantitatve assessment (PIFR) optimal PIFR
(lung deposition) inhaled drug particles17
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8 (peak inspiratory flow rate: PIFR) Inchek DIAL (Clement

Company, USA) liter per min optimal PIFR inhaler devices
3) asthma (Asthma co-morbidities)

(co-morbidities) asthma
difficult to treat asthma 51-95%

asthma rhinosinusitis, psychiatric disorders, gastro-esophageal
reflux,vocal cord dysfunction, obstructive sleep apnea allergic bronchopulmonary aspergillosis
(ABPA) difficult asthma
12
3.1 Rhinosinusitis, allergic & non allergic rhinitis nasal polyps
upper airway disease lower airway disease WHO
allergic rhinitis asthma allergic rhinitis impact on asthma (ARIA)18
subset severe asthma aspirin exacerbated respiratory disease (AERD)
rhinitis asthma aspirin intolerance nasal polyps
asthma systemic corticosteroid 19
rhinosinusitis asthma 70% allergic rhinitis sinusitis
spectrum chronic rhinosinusitis (CRS) chronic rhinosinusitis with nasal
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polyps (CRSwNP) chronic rhinosinusitis without nasal polyps (CRSsNP ) nasal polyps
inflammatory pattern CRSsNP neurtrophilic
inflammatory pattern Th1 mediated CRSwNP eosinophilic pattern Th2
mediated20 AERD nasal polyps 8.2 %
CRSsNP21 CRS nasal obstruction, nasal secretion, post nasal drip,
headache, facial pain amnosmia CT scan
sinus nasal endoscopy 12
Severe Asthma Research Program (SARP)
severe asthma 54% (sinus diseases) 27%
sinus rhinitis
asthma rhinitis rhinitis allergic

non allergic rhinitis asthma rhinitis asthma control
rhinitis
asthma ACQ
AQLQ rhinitis asthma outcome SARP cohort
71% asthma atopy skin prick test antigen 1
severe asthma atopy non severe asthma 22
sinus CT scan asthma mucosal sinus scores asthma
severity severe asthma maxillary, frontal ethmoid sinuses
SARP cohort
late onset severe asthma

sino-pulmonary infection22
Upper airway disease rhinosinusitis (CRS) nasal polyps
allergic rhinitis non allergic rhinitis asthma uncontrolled
asthma upper airway diseases

3.2 Psychiatric disorders
psychological distress psychiatric disoders
asthma psychological distress level of
depressive symptoms psychological disorders
asthma
(presence or absence clinical disoders) 23 psychiatric disorders asthma
2-3
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severe asthma non severe asthma mood disorders, major depressive disorders,
anxiety disorders, panic disorders specific phobia social phobia agoraphobia
psychological disorders
24
9 upper airway diseases lower airway disease
global airway diseases

psychological disorders (chronic diseases)
psychiatric disorders severe asthma
self maagement treatment adherence outcome
severity asthma25 psychiatric disorders
- General Health Questionnaire (GHQ) short form 12-item questionnaire
6 psychological disorders
exacerbation26
- Hospital Anxiety and Depression (HADS) 2 subscale Hospital Anxiety
Depression Anxiety Subscale (HADS-A) Hospital Anxiety Depression Depression Subscale
(HADS-D) HADS-A HADS-A asthma near
fatal asthma 27 HAD
psychiatric disorders asthma
psychological intervention asthma RCT
28
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psychiatric disorders

asthma
asthma outcome difficult asthma

10 psychiatric disorders asthma outcome 2 (bi-directional)
24
3.3 Gastro-esophageal reflux
GERD severe asthma asthma GERD
hyper-inflation intra-abdominal pressure gastric
contents esophagus lower esophageal sphincter
asthma systemic corticosteroid theophylline 2 agonist
esophageal sphincter tone co-morbidities obesity
GERD asthma 2 aspiration reflux
gastric contents trachea vagal reflex mediated esophageal
mucosal receptors low pH distension29 GERD esophageal
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symptoms extra-esophageal symptoms GERD (

) acid reflux pH difficult to control
asthma GERD pH abnormal
pH distal esophagus 44% proximal esophagus 24%30
abnormal esophageal pH asthma 12-85% symptomatic
GERD asthma 50-80%31 GERD laryngopharyngeal reflux (LPR)
regurgitation gastric content laryngopharynx layngopharyngeal symptoms
upper airway symptoms asthma
symptomatic GERD asthma

lung function GERD severe asthma
Cochrane review GERD asthma
asthma control29
3.4 Vocal cord dysfunction (VCD)
Vocal cord dysfunction (VCD) paradoxical vocal cord motion (PVCM)
asthma asthma VCD
severe asthma 12-50%

VCD paradoxical vocal fold closure inspiration variable
extra-thoracic airflow obstruction severe dyspnea VCD

VCD asthma high dose systemic corticosteroid
asthma exacerbation
asthma32
VCD 2.8% exertional dyspnea
14 33 VCD
psychiatric disorders, sexual abuse, gastroesophageal reflux disease irritant
exposure32 VCD direct visualization vocal cord
complete adduction vocal cords inspiration formation posterior glottis
clink paradoxical movement

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flow volume loop 25%

blunting inspiratory limb variable extra-thoracic obstruction
flow volume loop VCD asthma
VCD (co-existing) asthma VCD
asthma 33
VCD speech therapy
airway patency
GERD post nasal drip VCD
(psychotherapy), biofeedback Inhaled anti-cholinergic agents 33, 34
1 asthma, COPD vocal cord dysfunction (VCD)
( 34)
Asthma
COPD
VCD
Age of onset
Any age
Elderly smokers
Adolescent and young
Classical symptoms
Wheeze, dyspnea,
cough worse at night
Dyspnea on exertion
Dyspnea, chest
tightness and stidor
Relation to
respiratory cycle
Exhalation > inhalation Exhalation > inhalation Inhalation > exhalation
Localization of
symptoms
Deep in chest
Deep chest
Upper chest, through
Physical exam
during symptoms
Expiratory wheeze
posterior chest
Expiratory wheeze
(posterior chest)
Inspiratory wheezing,
stridor, upper chest
Chest film findings
Inflation, normal
Hyperinflation and
hyper-lucent lungs
Normal
Pulmonary function
Reversible airflow
Irreversible airflow
Extra-thoracic
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test (PFT)
obstruction with
normal DLCO
obstruction, low DLCO obstruction, normal

DLCO
Response to ICS
Good
Poor
Poor
Response to
bronchodilators
Good
Moderate
Poor
VCD asthma
asthma VCD endoscopy flow volume loop

A)
B)
C)
11 Flow volume loop A) B) tracheobronchomalacia notching

inspiratory and expiratory limb C) vocal cord dysfunction (VCD) truncation of inspiratory limb
D) fixed upper airway obstruction trucation inspiratory limb expiratory limb
3.5 Obstructive sleep apnea (OSA)
flow volume loop
Obstructive sleep apnea (OSA) asthma OSA
obesity asthma OSA bronchial hyper-reactivity (BHR) OSA
asthma 2
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1) Inflammation local (upper and lower airway) inflammation systemic

inflammation bronchial neutrophilic inflammation OSA
OSA systemic inflammatory cytokines oxidative stress
obesity Interleukin-6 pro-inflammatory cytokines
macrophages T lymphocytes obesity asthma OSA
C-reactive proteins adipocytes hepatocytes
IL-6 tumor necrosis alpha (TNF-) obesity sleep apnea
asthma35
2) Mechanical disadvantages obesity GERD reflex
vagal bronchoconstriction obesity elastic load OSA36
OSA uncontrolled asthma high dose systemic
corticosteroid uncontrolled asthma airway collapsibility
OSA uncontrolled asthma OSA
uncontrolled asthma obesity 37
OSA continuous positive airway
pressure (CPAP) OSA asthma
asthma controll 38 Meta-analysis CPAP asthma
rescue bronchodilator peak expiratory flow rate (PEFR)
bronchial hyper-reactivity OSA asthma
39
OSA
uncontrolled asthma obesity
local systemic inflammation mechanical problems
uncontrolled asthma uncontrolled asthma CPAP
3.6 Allergic broncho-pulmonary Aspergillosis (ABPA)

ABPA immunological diseases hyper-sensitivity
response Aspergillus fumigatus ABPA asthma
cystic fibrosis atopy ABPA airways
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asthma cystic fibrosis Aspergillus

ABPA asthma cystic fibrosis Patterson K.
ABPA 1-2%40 Argawal R. ABPA
12%41 Eaton T ABPA asthma 5.6%42 fungal
sensitization asthma asthma skin prick test
(SPT) Aspergillus fumigatus 21.6% SPT
HRCT chest ABPA 1 4
ABPA42 ABPA severe asthma Basich JE
corticosteroid dependent asthma
ABPA 15%43 ABPA asthma
severe uncontrolled asthma serum total IgE
1,000 IU/ml skin prick test specific IgE Aspergillus fumigatus
(exclude) ABPA total IgE 1000 IU/ml
systemic corticosteroid
SPT specific IgE Aspergillus fumigatus (asthma with
Aspergillus sensitization) total IgE HRCT central bronchiectasis (ABPACB) upper lobes 1 4 ABPA central bronchiectasis
HRCT ABPA-S ABPA serologic type44
ABPA systemic corticosteroid prednisolone 0.5 mg/kg
1-2 5-10 mg
total IgE (anti-fungal agents) itraconazole 200 mg 2
ABPA 4-6 40
anti-IgE omalizumab
ATS ERS severe asthma guideline 2013
severe asthma ABPA9
ABPA asthma fungal sensitization
asthma
skin prick test specific IgE A fumigates total IgE HRCT
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12 asthma fungal sensitization Aspergillus fumigates sensitization allergic

asthma with fungal sensitization (AAFS), severe asthma with fungal sensitization (SAFS), allergic
bronchopulmonary aspergillosis-serology (ABPA-S) allergic bronchopulmonary aspergillosiscentral bronchiectasis (ABPA-CB) ( 44)
Difficult asthma (Investigation in difficult asthma)
difficult asthma
1) Lung function test

GINA airway obstruction
fluctuation airway obstruction bronchodilator reversibility bronchial
provocation test1 spirometry bronchodilator response
fixed airflow obstruction exclude asthma airway remodeling asthma severe asthma

fixed airway obstruction
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13 ABPA bronchiectasis high attenuation mucus (HAM)

mucus plugging airways
fixed airflow obstruction adult
onset asthma high sputum eosinophils bronchial hyper-responsiveness9, 12 lung volume
measurement air trapping severe asthma DLCO
asthma DLCO emphysema
DLCO
gas exchange asthma lung fibrosis
lung function test
difficult asthma

1.1 asthma small airway obstruction
1.2 asthma fixed airway obstruction
asthma small airway obstruction small airways noncartilagenous
airway 2 mm severe asthma small airway resistance
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FEF25-75% peripheral airway function

large airway premature airway closure FVC
(lung volume measurement) air-trapping
inspiratory capacity (IC) RV/TLC impulse oscillation system
(IOS) asthma central respiratory resistance
severe asthma peripheral airway resistance small
airway function asthma 12, 45
1 peripheral airway resistance FEF25-75%= forced expiratory flow at 2575% of forced vital capacity, R5 and R20 = Resistance of respiratory system at frequency of 5 Hz
and 20 Hz, Ax = reactance area, X5 = reactance of respiratory system at 5 Hz, Fres = resonance
frequency of reactance
Methods
Parameters indicate small airways dysfunction
Spirometry
FEF25-75% , FEF50% , FVC/SVC
IOS
R5-R20, AX, X5, Fres
Body pletysmography
RV/TLC, FRC, RV
HRCT
Air trapping
Inhomogeneity of ventilation
VA/TLC
small airway function

FOT/IOS 2
asthma fixed airway obstruction fixed airflow obstruction
bronchodilator agents bronchodilator reversibility
FEV1/FVC ratio lower limit normal stable phase high
dose ICS (fluticasone > 1000 mcg ) asthma
oral corticosteroid leukotriene modifier fixed airflow
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obstruction late onset asthma

non atopic asthma fungal sensitization (Aspergillus fumigatus) occupational exposure12
14 Forced oscillation technique impulse oscillometry (IOS) airway

resistance (A) resistance of respiratory system at 5 Hz 20 Hz (R5-R20)
25% R5 peripheral airway resistance B) reactance 5 Hz
rapid acting bronchodilator (C) Fres (Resonace frequency of reactance) severe asthma
2) (Imaging studies)
(co-morbidties)
chest radiograph hyper-inflation bronchial wall
thickening
HRCT parenchymal lung disease sarcoidosis,
pulmonary fibrosis, bronchiectasis, bronchiolitis
uncontrolled asthma central bronchiectasis hyper-attenuation mucus
HRCT severe asthma HRCT severe asthma
6
2.1) (qualitative) airways HRCT asthma
bronchiectasis severe asthma bronchiectaisis
severe asthma 30% (
9-77%)46
CT scan
bronchiectasis bronchiectasis asthma
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HRCT bronchial
dilatation asthma bronchial diameter
pulmonary arteriole diameter reflex hypoxic
vasoconstriction asthma bronchiectasis severe asthma comorbidity bronchiectasis
airway remodeling asthma
asthma
bronchial wall thickening (BWT) HRCT
2 small airway dysfunction IOS-FOT

Spirometry
Main principle flow sensor/volume

displacement flow
rates lung volumes
FOT/IOS
Forced oscillations single
frequency sound waves (FOT)
impulses
(IOS)
pressure waves respiratory
resistance reactance
Zrs, Rrs, Xrs, Fres, Ax
(Main parameters) Volumes: FEV1, FVC

Flows: PEFR, FEF2575%
(+++)
(+)
Patient co-operation
(breathing Forced exhalation
Tidal breathing
maneuver)
35%
515%
(Sensitivity to airway location)
Central
+
+++
Peripheral ++
+++
bronchodilator
1215% FEV1
40% R5 or X5
response
bronchoconstrictor 20% FEV1
50% R5
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response
lung mechanics
+
+++
+++
++
HRCT asthma bronchiectasis

HRCT 47, 48
- mosaic attenuation
- mucus plugging
- prominent centrilobular opacities
- atelectasis
- pulmonary emphysema ( )
tracheobronchomalacia
15 Expiratory collapse trachea tracheomalacia cross sectional area
50% B A
2.2) large airways (quantitative assessment of large airway)
large airways HRCT severe asthma
software
12, 49 airway lumen Hounsfiled Unit (HU)
cut-off -500 HU airway dimension Full-width at half maximum principle
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(FWHM) percent wall area ( wall area total area) per cent wall
thickness ( wall thickness total diameter)
2.3) small airway resistance air trapping
Small airway resistance severe asthma asthma
small airway resistance
HRCT small airway function lung
parenchyma ventilation reflex hypoxic vasoconstriction
perfusion lung attenuation HRCT expiratory CT scan
12, 50
air trapping HRCT
- low attenuation area (LAA) -850 HU functional residual

capacity (FRC)
- per cent pixels attenuation -900 HU expiratory scan
- mean lung density expiratory to inspiratory ratio
- lung attenuation inspiration expiration
16 airway wall thickness bronchial wall thickenss (BWT) HRCT

air trapping HRCT severe asthma
ATS air trapping
exacerbation
air trapping HRCT severe asthma phenotype
inhaled corticosteroid particles ultra-fine particle ICS
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asthma small airway dysfunction inhaled corticosteroid

51
oral leukotriene modifiers montelukast systemic
corticosteroid systemic effect small airways severe asthma 52
17 extension air trapping asthma HRCT low attenuation

area (LAA) extension LAA area
A = 0%,
B 25%,
C
D 25-50%, E 50-75% F 75%
serum immunoglobulin E (IgE) complete blood count

eosinophils IgE difficult asthma
ABPA ABPA
serum total IgE 1000 IU/ml total serum IgE
omalizumab severe allergic asthma peripheral blood eosinophilia
asthma 1500/mm3 hyper-eosinophilic syndrome Churg
Strauss Vasculitis (Eosinophilic Granulomatosis with polyangiitis: EGPA) 53
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3.1 allergic testing

allergic testing in vitro test specific IgE (sIgE)
antibody (allergens) Enzyme link immunoabsorbant assay (ELISA)
antibody kAU/L probability allergy
in vivo test skin prick test (SPT)
allergy test
(clinical context) allergy test allergic
asthma environmental allergen house dust mite
mite allergy54 allergic test severe allergic
asthma anti-IgE omalizumab
3
Skin prick test ()
Serum specific IgE ()
(Greater sensitivity)
(Measure biological response)

(Less expensive)
(Rapid result)
(Not affect by
antihistamine)
(Not affect by skin
disease)
(No risk of anaphylaxis)
(Widely available)
specific IgE IgE antibody allergen D. pteronyssinus, D

farinae, cockroach antigen, animal danders specific IgE radioallergoabsorbant test assay ImmunoCap (Sweden) Immunocap Allergens
< 0.1 kAU/L screening ImmunoCap Phadiatop for mixed respiratory allergen
0.35 kAU/L specific IgE antibodies allergen allergen sensitiization
symptomatic allergy
serum total IgE IU/ml 1 IU 2.4 ng protein total IgE
allergy serum total IgE
non atopic asthma atopic asthma 55
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18 General model specific IgE antibody slope

curve , atopy, allergen
load sensitizing allergens
3.2) exhaled nitric oxide (FeNO)
FeNO surrogate airway inflammation nitric oxide
arginine nitric oxide citruline nitric oxide syntheases (NOS)
inducible form (INOS NOS2) pro-inflammatory cytokines
FeNo
reproducibility FeNo
ICS asthma FeNo 85%
50-90% asthma ICS ATS standardization of
measurement exhaled nitric oxide FeNo asthma 56
FeNo asthma
57 meta-analysis FeNO
(tailor treatment) asthma (clinical symptoms)
FeNo
ICS ICS
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FeNo moderate to severe asthma mild

asthma range 58 FeNo
asthma sputum eosinophils, exacerbation,
atopy, hyperinflation bronchial hyper-reactivity
American Thoracic Society European Respiratory Society severe
asthma 2013 computed tomography of
chest, sputum eosinophil count exhaled nitric oxide
(evidence based) 9
4 severe asthma ATS/ERS guideline on
definition, evaluation and treatment of severe asthma 2013 ( 9)
High
resolution
computed
tomography
(HRCT)
sputum
eosnophil
count
severe asthma
HRCT
atypical
presentation
sputum eosnophil
clinical criteria

sputum eosinophil count
FeNO
exhaled nitric
oxide (FeNo)
Atypical presentation severe asthma

excessive mucus production, rapid
declined lung function, reduced DLCO
ABPA

standardization

asthma
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Difficult asthma
5 difficult asthma ( 12)
Spirometry (pre and

post bronchodilator
FEV1) and flow volume
loop
Acute bronchodilator
reversibility with rapid
acting acting
bronchodilator
Atopic test (Skin prick

test or specific IgE
measurement)
skin prick
test

specific IgE 76-83%
Bronchial provocative spiromerty

test methacholine asthma
challenge test (MCT)
challenge test
High resolution
atypical
computed tomography presentations chroncic
(HRCT)
sputum production rapid
decline FEV1
Exhaled nitric oxide
ATS/ERS severe asthma

Low FEV1 future risk of
exacerbation
persistent airflow limitation
FV- loop upper airway
obstruction large airway obstruction
asthma COPD
FEV1 400 ml
12%
(normal lung
function ceiling effect)
non-atopic asthma
atopic asthma allergen
sensitizer
(allergen) SAFS, ABPA
work
related asthma non asthmatic
eosinophilic bronchitis (NAEB)
asthma EIB MCT
asthma COPD
bronchiectasis
bronchial wall thickness (BWT) HRCT
emphysematous type
COPD
eosionophils
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(FeNo)
Induced sputum (IS)
guideline 2013

center
Salivary or urine
cotinine
Prednisolone (cortisol)
and theophylline serum
level
sputum
ICS
inflammatory phenotype
asthma
eosinophilic,neutrophilic,mixed cellular
paucigranulocytic asthma

active passive smoking
(ETS)
adherence oral
inhaled corticosteroid theophylline
Difficult asthma (Management of difficult asthma)

difficult asthma
asthma alternative diagnosis

asthma asthma (co-morbidities)
( )
asthma high intensity treatment

treatment resistant asthma (intrinsic asthma disease activity)12
target treatment non-pharmacological therapies
severe refractory asthma treatment resistant asthma (TRA)
12
1)
2)
3)
4)
New biologic treatment of asthma

Non-corticosteroid anti-inflammatory drugs
Improvement of corticosteroid insensitivity
Bronchial thermoplasty
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New biologic agents of asthma

1) Anti-IgE (Omalizumab) anti-IgE therapy omalizumab biologic agent
(approved) asthma step 5 GINA guideline
IgE
atopic asthma omalizumab
IgE monoclonal antibody free IgE FCRI high affinity
receptors mast cells basophils
medicators cytokines anti-IgE asthma
exacerbation allergic asthma
severe asthma non allergic asthma
omalizumab IgE mediated asthma59 asthma
biologic agents
5-10% asthma
2) Cytokines and chemokine targeted approach asthma (overlapping

cytokines asthma
and redundancy)
Th2 cytokines interleukin-4, Interleukin-5

interleukin-13
cytokines 3 60
17 Novel therapies severe asthma inflammatory cascade (

12)
a) Blocking antibodies cytokines chemokines
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250
b) Soluble receptors receptor antagonist cytokines cytokines

receptors
c) Inhibition specific signal transduction cytokines
(downstream signaling)
6 Targeted therapy Th2 inflammation severe asthma
phase III clinical studies
Targeted therapy
Anti-IL5
IgG humanized
antibody62, 63
mAb IL-13
eosinophils
recruitment
eosinophil
activation
Anti-Il-13
IgG4 humanized m
antibody64
Ab IL-13
Study design
Mepolizumab IV 75 mg, 250
(phase III)
mg, 750 mg
/mo severe
asthma sputum
eosinophillia
12
Lebrikizumab SC 250 mg/mo
(phase III)
6
Soluble IL-4
receptors65 66
Pitrakinra (IL-
4& IL-13
nebulize form
mutein) SC
Aerovant
(Phase III)
IL-4 receprtor
antagonist
IL-13
IL-4 IL-4
receptors
IgE
synthesis B
cells
2559
Outcome
sputum
eosinophils
LAR
clinical
significant
exacerbation
FEV1 8.1%
high serum
periostin
placebo
ACQ, PEFR
late phase
asthmatic response
allergen mild
asthma patients
251
cytokines or chemokine targeted approach asthma anti-IL5 antibody, Inhibition of IL-4 receptors, anti-IL-13, inhibition of eotaxin, anti-tumor necrosis-,
Interferon- inhibition administration60
Targeted therapies monoclonal antibodies soluble receptors severe
asthma 661
3) Non-corticosteroid anti-inflammatory drug
inhaled corticosteroid asthma
severe asthma macrolide azoles
selective PDE4 inhibitors cyclosporine methotrexate 12
macrolide severe asthma neurtophilic asthma antiinflammatory effect imunomodulatory effect67 ATS/ERS severe asthma
guideline 2013 macrolide antibiotics asthma bronchitis
sinusitis acute bacterial infection9 antifungal agents severe asthma
ABPA drug interactions 68 ATS/ERS
guideline antifungal agents severe asthma ABPA
fungal sensitization skin prick test specific IgE 9
methotrexate severe asthma oral corticosteroid (steroid
dependent asthma) oral corticosteroid steroid sparing effect ATS/ERS
severe asthma guideline
9 selective PDE4 inhibitor roflumilast
asthma late asthmatic reaction (LAR) allergen 69
ICS beclomethasone roflumilast
selective PDE4 inhibitors asthma 70
Improve corticosteroid insensitivity
corticosteroid insensitivity severe asthma

corticosteroid insensitivity severe asthma COPD
12
1) Mitogen-activated protein kinase activity (MAPK) p38 MAPK activation
phosphorylation transcription factor NF-kB p65 subunit71 MAPK gene
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252
transcription CXCL8 neutrophil chemotactic factor monocyte chemotactic

peptide (MCP-1) corticosteroid
2) glucocorticoid receptor corticosteroid 72
3) Oxidative stress HDAC-2 activity oxidative stress
pollution smoking low dose theophylline
HDAC activity low dose theophylline corticosteroid
asthma 73, 74
Bronchial thermoplasty
airway smooth muscle severe asthma
bronchial thermoplasty
(radiofrequency heat energy) muscle
mass airway smooth muscle
bronchial thermoplasty peak expiratory flow rate symptoms severe
asthma75 double blind control study bronchial thermoplasty
exacerbation shamed intervention
bronchial thermoplasty
76 ATS/ERS severe asthma guideline bronchial thermplasty
asthma exacerbation
severe airflow
obstruction systemic corticosteroid 9
Difficult asthma
(modifiable factors)
difficult asthma refractory asthma treatment resistant asthma
high intensity asthma refactory asthma (intrinsic
disease activity) novel treatments biological markers
personalized therapies
2559
253

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Controversial Issues

3. Omalizumab (Anti-IgE in Severe Allergic Asthma)..... 51

6. Small airway diseases in asthma: Is it really that small? ... 99

12. Chronic Eosinophilic Pneumonia .. 201

13. difficult severe asthma 215

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

2.2 (well-designed, non- randomized

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

1.1 PEF 60 L/min 20

Controversial Issues in Asthma 2016

Upper airway obstruction

Wheezing aggravated by forced

Posterior wall of airway

Controversial Issues in Asthma 2016

Vocal cord dysfunction

PEF or FEV1 / PEF variability

> 80% / < 20%

> 80% / < 20-30%

Controversial Issues in Asthma 2016

(Risk factors for poor asthma outcome)

Controversial Issues in Asthma 2016

(Poor asthma outcome)

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Asthma education, environmental control, influenza vaccine and pulmonary rehabilitation

As needed rapid-acting 2-agonist

Add one or both

1 (asthma treatment level)

( RABA = rapid acting 2 agonist, ICS = inhaled corticosteroid, ICS/LABA = inhaled

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

beclomethasone, budesonide, fluticasone

(Stepping down asthma treatment when achieved control)

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

(Easy Asthma Clinic)13 .. 2547

Controversial Issues in Asthma 2016

Easy Asthma Clinic

Controversial Issues in Asthma 2016

oxygen saturation (room air)

< 90% or cyanosis

PEF > 50% predicted or best

PEF < 50% predicted or best

Controversial Issues in Asthma 2016

RABA short-acting anticholinergic

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

(Asthma and obesity)

Controversial Issues in Asthma 2016

Aspirin-exacerbated respiratory disease (AERD)

(Asthma and surgery)

Controversial Issues in Asthma 2016

(Asthma-COPD overlap syndrome or

AsthmaCOPD overlap syndrome ACOS 15-5084

Controversial Issues in Asthma 2016

Controversial Issues in Asthma 2016

Patient age 6 years ?