Difficult Asthma

Prof Peter G Gibson

Centre for Asthma and
Respiratory Diseases
Newcastle Australia

Asthma shouldnt be
difficult, because ..
Modern pharmacotherapy
Controls
Airway inflammation
and
Variable airflow obstruction

Asthma shouldnt be
difficult,

But sometimes it is..

Severe Persistent Asthma

in Asia
18
16
14
12
10
8
6
4
2
0
Malaysia

Singapore Hong Kong

P'pines

China

Zainudin BMZ etal, Respirology 2005;10:579

Names for difficult asthma

Severe refractory asthma
Difficult to control asthma
Brittle asthma
Severe asthma
Therapy-resistant asthma
Steroid-dependent asthma

Difficult Asthma: what is it ?

Symptomatic despite maximal doses of

ICS+Long-acting bronchodilator:
B2, theophylline, for 6 months

Persistent daily symptoms

Frequent exacerbations

Requires oral steroid for control

Maintenance
Frequent courses

GINA 2006: Asthma treatment steps

as needed rapidacting 2-agonist

Oral
glucocorticosteroid
(lowest dose)
*in children <6yrs:
moderate-dose ICS
anti-IgE
antibodies

Difficult Asthma
Vocal Cord Dysfunction
Noninvasive markers to identify
and adjust therapy
Single patient controlled trials of
therapy

Difficult Asthma Clinic

Diagnosis
of Asthma
excluded
and
discharged
Control
Achieved
and
Discharged

Referred to DAC

Confirm Diagnosis

Identify and Manage Aggravating Factors

Optimise Asthma Management Skills

Control
Achieved
and
Discharged
or remain
under DAC

Trial Add on Therapies

1
2
3

Control
Achieved
and
Discharged
Control
NOT
Achieved
and remain
under the
care of DAC

Assessment
Diagnosis: is it asthma ?
Risk profile: will this person die from
their disease?
Triggers
Complications
Asthma management skills

Is it asthma ? Or
COPD
Bronchiectasis
VCD
Hyperventilation
Obesity
Pulmonary hypertension
Churg Strauss vasculitis

Vocal Cord dysfunction

1842 Dunglison: hysteria causing disorder of

laryngeal muscles
1869 Mackenzie: visualised VC in hysteric
adults with stridor and saw PVCM
1902 Osler: defined condition. spasms of
laryngeal muscles times of great distress
1983 Christopher: Vocal cord dysfunction
mimicing asthma, objective measurement
NEJM

VCD and Difficult Asthma

VCD masquerades
as asthma

Frequent OCS
Same meds as
severe asthma

VCD and asthma coexist

60
50
40
30
20
10
0
VCD
alone

Newman KB, AJRCCM 1995 152:1382

& OCS

VCD +
asthma

VCD: objective
confirmation

Figure 1: FOL view of

inspiratory adduction
of the vocal cords

Figure 2A: normal inspiratory curve

Figure 2B: attenuated inspiratory curve

VCD: history
Symptoms
Dyspnea: inspiratory
Voice symptoms
Tightness: throat
Pain: throat
Nonresponse
B2agonist
Sensory
hyperresponsiveness

Associated diseases
Gerd
Rhinosinusitis
Asthma (!)

VCD: tests

Spirometry:
restrictive, normal
SaO2: normal
Flow vol: variable
extrathoracic AFO
Laryngoscopy:
paradoxical vocal
cord movement

Provocation:

4.5% saline
FEV1
Inspiratory flow loop
Laryngoscopy

Vocal function

S to Z ratio
Max. phonation time

Inspiratory-expiratory volume- flow

loop
after saline or EIA challenge

Flow volume loop in VCD

Maximum phonation time

P < .001

18
16
14
12
10
8
6
4
2
0
CC + VCD

VCD

CC Alone

Voice
Disorders

Normal
Controls

Improvement in Symptom
Scores
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
Breathing
p<.001

Cough
p=.003

Voice
p = .049

Treatment

Upper
airway
p=.034

Limitation
p=.011

Placebo

Vertigan Thorax 2006

1.5
Percent

Seconds

1
0.5
0

Treatment p=.018 *

Placebo p=.283

1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0

Treatment p=.041*

3
2.5
2
1.5
1
0.5
0
-0.5
-1
-1.5

Treatment p=.003 *

Placebo p=.222

Improvement in harmonic to noise ratio p =

.173

Placebo p=.193

Improvement in jitter p=.051

Semitones

Decibels

Improvement in maximum phonation

time p = .348
3
2.5
2
1.5
1
0.5
0

Treatment p=.044 *

Placebo p=.539

Improvement in phonation range

p=.201

Effect of speech pathology treatment for VCD vertigan Thorax 2006

VCD
Clinical

features: symptoms
Assessment: FOL; flow/vol
Treatment: speech therapy
Mechanisms: irritable larynx

High Risk Profile

Severe exacerbations
Intubation/ICU
Food allergy
Brittle pattern
Psychiatric disease

Asthma management skills

2.
3.
4.
5.

Understanding
Inhaler technique
Self-monitoring
Action plan
Adherence

40
35
30

(%) percent

1.

25
20
15
10
5
0
Did Not Complete

Achieved Control with Education

Difficult asthma:
Complications
Osteoporosis
Steroid myopathy
Depression
Obesity
VCD
Diabetes mellitus

GINA 2006: Asthma treatment steps Education

Environmental
control
Complications

as needed rapidacting 2-agonist

Oral
glucocorticosteroid
(lowest dose)
*in children <6yrs:
moderate-dose ICS
anti-IgE
antibodies

Assessment
Diagnosis: is it asthma ?
Risk profile: will this person die from
their disease?
Triggers
Complications
Asthma management skills

Difficult Asthma Clinic Model

Step 6
Step 5
Step 4
Step 2

Step 3

Poor Control
Continues

Poor Control
Continues

DAC

DAC

and

ongoing

Poor
Control
Continues
Triggers and
aggravating
factors
Removed or
Managed

Optimisation of
Therapy and
Education

Omalizumab

OCS

Step 1
Confirm
diagnosis

Trial of Add
on
Therapies

LTRA
MTX

Very mild

Mild

Moderate
Gold

Severe

Eosinophilic Sputum

Non-eosinophilic Sputum

Inflammatory Phenotypes in
Stable Persistent Asthma, on ICS

31%

41%

Eosinophilic
Neutrophilic
Paucigranulocytic

59% Non
eosinophilic

28%

Simpson J et al, Respirology 2006;11:54-61

Treatment response depends on

inflammatory phenotype

Meijer Clin Exp Allergy 2002

Green R, etal, Lancet 2002

Difficult asthma with

eosinophilic bronchitis

ICS/LABA :adherence !!
OCS: trial
LTRA: add on montelukast
Maintenance OCS: dose adjustment by
sputum eos, [adherence !!!]
Itraconazole for ABPA
Oral gold/ methotrexate
Parenteral steroid

Induced Sputum eosinophils in ABPA: placebo vs Itraconazole

Wark PAB etal JACI
Eosinophils %
12
10
8
6
4
2
0

Itraconazole

Placebo

4
Visits

Difficult asthma with

noneosinophilic bronchitis
ICS/LABA
Triggers:

smoking
infection

Macrolide
? Theophylline
?TNFa

Allergens

Acquired
Immunity

Particulates, Pollutants, Virus,

Endotoxin, Bacteria

IgE
Activated TH2 Cells

TLR
Macrophages and Epithelial Cells

ICS X
Eosinophilic
Asthma

Innate
Immunity

X LABA
Neutrophilic
Asthma

Inflammatory cell activation

X LABA
hyperresponsiveness

LABA reduces Neutrophilic

Inflammation
1600
1400

1200
1000

800

0 wks
4 wks

600
400

75

200

70

0
IL-8

PMN

Barnes PJ, Chest 2005

128:1936

65
60
55
IL-8

Reid DW, ERJ, 2003

Stable Asthma, no ICS

nonsmokers

smokers

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0
EA

NEA

EA

NEA

Chalmers, CHEST 2001

RCT of macrolide vs placebo in

refractory noneosinophilic asthma

Symptomatic Asthma
AHR to hypertonic
saline
Severe Persistent
asthma according to the
2002 GINA guidelines
No sensitivity to
macrolide antibiotics
Clarithromycin
Simpson J etal Respirology

Study Design
V1

V2

V3

V4

V5

CAM 1000mg
Screening

Follow Up

Placebo
t=-4

t=0

t=8

t=12

CAM reduces IL-8 Protein

PLACEBO

12

12

10

10

8
6
4

Sputum IL-8 ng/mL

Sputum IL-8 ng/mL

ACTIVE

8
6
4

0
Before

* p= 0.0046 versus visit 2

After

Before

After

Improved Quality of Life

0.8

0.7

Quality of Life Score

0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1

Macrolide Treatment
Placebo
* p=0.016 versus placebo

Difficult Asthma Clinic Model

Step 6
Step 5
Step 4
Step 2

Step 3

Poor Control
Continues

Poor Control
Continues

DAC

DAC

and

ongoing

Poor
Control
Continues
Triggers and
aggravating
factors
Removed or
Managed

Optimisation of
Therapy and
Education

Omalizumab

OCS

Step 1
Confirm
diagnosis

Trial of Add
on
Therapies

LTRA
MTX

Very mild

Mild

Moderate
Gold

Severe

Still not controlled

Modified n=1 trials
Using expensive drugs

Montelukast
Omalizumab
IVIG

Toxic drugs

Oral gold
Methotrexate

Design
ICS Sub group
Vi si t 1 Vi si t 2 Vi si t 3 Vi si t 4 Vi si t 5 Vi si t 6

Vi si t 7

week-2

week16 week20 week24 week28

week0

week2

week4

Run-in

week8

week12

Xolair

Vi si t 8 Vi si t 9 Vi si t 10

Monit oring

OCS Sub group

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5

Visit 6 Visit 7 Visit 8 Visit 9 Visit 10 Visit 11 Visit 12 Visit 13 Visit 14

week-2 week0

week12 week16 week20 week24 week28 week32 week36

Run-in

week2 week4 week8

Xolair

Xolair

and

wean

OCS

week40

Monitoring

week44

Difficult Asthma

Diagnosis: is it
asthma
Risk profile: will this
person die from
their disease?
Triggers
Complications
Asthma
management skills

Treatment
ICS/LABA
Eos
Neut
N=1 trials

Thankyou !

Case 2 Mr RG

34 yo male
Severe asthma since childhood
OCS dependant: since early childhood
Hospitalisations - 245 since birth
Hospitalisations in the last 12/12
No ICU admissions
1 HDU admission 2002
Respiratory Specialists

Paediatricians: n=1
Adult: n=1

SAC Assessment
Oesteoporosis
Depression
Steroid Myopathy
Cataracts

Treatment

Fluticasone/Salmeterol 500/50 2bd

Prednisolone 50mg daily
Salbutamol 5mg qid
Salbutamol 100mcg 2-4 prn
Methotrexate 25mg IMI weekly
Folic acid 5mg twice weekly
Alendronate sodium 70mg/week
Fluoxatine 40mg daily

Prior treatment failure to:

Montelukast
Theophylline
Auranofin

Baseline Characteristics
Weight 64kg
IgE -31

FEV1 2.49 (74% predicted)

VC 3.36 (86%)
ACQ 3.2/7
AQLQ 4.45

FEV1

2.5

1.5
1
0.5
0
Baseline

60

mg of Prednisolone

Litres

Omalizumab

Omalizumab
and OCS
Weaning

Off
Omalizumab

OCS Dose

50
40
30
20
10
0
Baseline

On Omalizumab Omalizumab and Off Omalizumab

OCS Weaning

Asthma Control Scores

Poor Control

7
6
5
4
3
2
1
Good

Control

Good QOL

Baseline

Omalizumab

Omalizumab and
OCS Weaning

Off Omalizumab

Asthma QOL

7
6
5
4
3
2
1

Poor QOL 0

Baseline

Omalizumab

Omalizumab and Off Omalizumab

OCS Weaning

Admissions
4

Number of Admissions

3.5
3
2.5
2
1.5
1
0.5
0
52/52 pre Rx On Rx (12/52) On Rx OCS Off RX (25/52) On Rx (16/52) off Rx (60/52) on Rx 34/52)
wean (12/52)

XRE Responder Evaluation RG

1/12 Pre
trial
FEV1

1.42L

FENO
QOL
ACQ
IgE
OCS

50mg

Dose 1
21/3/0
6
0.94L
5.5
2.67
6.14
35
100mg

Dose 2
18/4/0
6
1.18L
8.2
4.13
4.28
49
50mg

Dose 3
23/5/06
2.12L
9.1
4.61
3.71
60
50mg
alternat
e days

Now
Nov 06
1.85L

50mg

Diagnosis: is it
asthma
Risk profile: will this
person die from
disease?
Triggers
Complications
Asthma
management skills

Treatment
ICS/LABA
Eos:
Neut
N=1 trials

Other issues

B2 agonist toxicity

Genotype
Long acting Ach: tiotropium

High dose b2: formoterol

education
GINA 2006: Asthma
Asthma
treatment steps
Environmental control

as needed rapidacting 2-agonist

Oral
glucocorticosteroid
(lowest dose)
*in children <6yrs:
moderate-dose ICS
anti-IgE
antibodies