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Difficult%20Asthma

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Max. phonation time. Inspiratory-expiratory volume- flow loop. after saline or EIA challenge ... Maximum phonation time. P .001. Improvement in Symptom Scores ... – PowerPoint PPT presentation

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Title: Difficult%20Asthma


1
Difficult Asthma
  • Prof Peter G Gibson
  • Centre for Asthma and Respiratory Diseases
  • Newcastle Australia

2
Asthma shouldnt be difficult, because ..
  • Modern pharmacotherapy
  • Controls
  • Airway inflammation
  • and
  • Variable airflow obstruction

3
Asthma shouldnt be difficult,
But sometimes it is..
4
Severe Persistent Asthma in Asia
Zainudin BMZ etal, Respirology 200510579
5
Names for difficult asthma
  • Severe refractory asthma
  • Difficult to control asthma
  • Brittle asthma
  • Severe asthma
  • Therapy-resistant asthma
  • Steroid-dependent asthma

6
Difficult Asthma what is it ?
  • Symptomatic despite maximal doses of
    ICSLong-acting bronchodilator B2,
    theophylline, for 6 months
  • Persistent daily symptoms
  • Frequent exacerbations
  • Requires oral steroid for control
  • Maintenance
  • Frequent courses

7
GINA 2006 Asthma treatment steps
8
Difficult Asthma
  • Vocal Cord Dysfunction
  • Noninvasive markers to identify and adjust
    therapy
  • Single patient controlled trials of therapy

9
Difficult Asthma Clinic
Diagnosis of Asthma excluded and discharged
Control Achieved and Discharged
Control Achieved and Discharged
Control NOT Achieved and remain under the care of
DAC
Control Achieved and Discharged or remain under
DAC
10
Assessment
  • Diagnosis is it asthma ?
  • Risk profile will this person die from their
    disease?
  • Triggers
  • Complications
  • Asthma management skills

11
Is it asthma ? Or
  • COPD
  • Bronchiectasis
  • VCD
  • Hyperventilation
  • Obesity
  • Pulmonary hypertension
  • Churg Strauss vasculitis

12
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

13
VCD and Difficult Asthma
  • VCD masquerades as asthma
  • Frequent OCS
  • Same meds as severe asthma
  • VCD and asthma co-exist

Newman KB, AJRCCM 1995 1521382
14
VCD objective confirmation
Figure 1 FOL view of inspiratory adduction
of the vocal cords
Figure 2A normal inspiratory curve Figure 2B
attenuated inspiratory curve
15
VCD history
  • Symptoms
  • Dyspnea inspiratory
  • Voice symptoms
  • Tightness throat
  • Pain throat
  • Nonresponse B2agonist
  • Sensory hyperresponsiveness
  • Associated diseases
  • Gerd
  • Rhinosinusitis
  • Asthma (!)

16
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

17
Inspiratory-expiratory volume- flow loop after
saline or EIA challenge
18
Flow volume loop in VCD

19
Maximum phonation time
P lt .001
20
Improvement in Symptom Scores
Vertigan Thorax 2006
21
Effect of speech pathology treatment for VCD
vertigan Thorax 2006
22
VCD
  • Clinical features symptoms
  • Assessment FOL flow/vol
  • Treatment speech therapy
  • Mechanisms irritable larynx

23
High Risk Profile
  • Severe exacerbations
  • Intubation/ICU
  • Food allergy
  • Brittle pattern
  • Psychiatric disease

24
Asthma management skills
  • Understanding
  • Inhaler technique
  • Self-monitoring
  • Action plan
  • Adherence

25
Difficult asthma Complications
  • Osteoporosis
  • Steroid myopathy
  • Depression
  • Obesity
  • VCD
  • Diabetes mellitus

26
GINA 2006 Asthma treatment steps
27
Assessment
  • Diagnosis is it asthma ?
  • Risk profile will this person die from their
    disease?
  • Triggers
  • Complications
  • Asthma management skills

28
Difficult Asthma Clinic Model
Step 6
Step 5
Step 4
Step 3
Step 2
Poor Control Continues DAC and Omalizumab
Poor Control Continues DAC ongoing
Poor Control Continues Trial of Add on
Therapies OCS LTRA MTX Gold
Triggers and aggravating factors Removed or
Managed
Optimisation of Therapy and Education
Step 1
Confirm diagnosis
Very mild
Mild
Moderate
Severe
29
Eosinophilic Sputum
Non-eosinophilic Sputum
30
Inflammatory Phenotypes in Stable Persistent
Asthma, on ICS
41
31
59 Non eosinophilic
28
Simpson J et al, Respirology 20061154-61
31
Treatment response depends on inflammatory
phenotype
Meijer Clin Exp Allergy 2002
32
Green R, etal, Lancet 2002
33
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

34
Induced Sputum eosinophils in ABPA placebo vs
Itraconazole Wark PAB etal JACI
Eosinophils
12
10
8
6
4
2
0
2
3
4
5
6
Itraconazole
Visits
Placebo
35
Difficult asthma with noneosinophilic bronchitis
  • ICS/LABA
  • Triggers
  • smoking
  • infection
  • Macrolide
  • ? Theophylline
  • ?TNFa

36
Particulates, Pollutants, Virus, Endotoxin,
Bacteria
Allergens
Acquired Immunity
Innate Immunity
IgE
TLR
Macrophages and Epithelial Cells
Activated TH2 Cells
ICS X
X LABA
Neutrophilic Asthma
Eosinophilic Asthma
Inflammatory cell activation
X LABA
hyperresponsiveness
37
LABA reduces Neutrophilic Inflammation



Barnes PJ, Chest 2005 1281936
Reid DW, ERJ, 2003
38
Stable Asthma, no ICS
nonsmokers
smokers
Chalmers, CHEST 2001
39
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
40
Study Design
V1
V2
V3
V4
V5
CAM 1000mg
Follow Up
Screening
R
Placebo
t-4
t0
t8
t12
41
CAM reduces IL-8 Protein
ACTIVE
PLACEBO

p 0.0046 versus visit 2
42
Improved Quality of Life

Macrolide Treatment
Placebo
p0.016 versus placebo
43
Difficult Asthma Clinic Model
Step 6
Step 5
Step 4
Step 3
Step 2
Poor Control Continues DAC and Omalizumab
Poor Control Continues DAC ongoing
Poor Control Continues Trial of Add on
Therapies OCS LTRA MTX Gold
Triggers and aggravating factors Removed or
Managed
Optimisation of Therapy and Education
Step 1
Confirm diagnosis
Very mild
Mild
Moderate
Severe
44
Still not controlled
  • Modified n1 trials
  • Using expensive drugs
  • Montelukast
  • Omalizumab
  • IVIG
  • Toxic drugs
  • Oral gold
  • Methotrexate

45
Design
ICS Sub group
OCS Sub group
46
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
  • N1 trials

47
Thankyou !
48
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 n1
  • Adult n1

49
SAC Assessment
  • Oesteoporosis
  • Depression
  • Steroid Myopathy
  • Cataracts

50
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

51
Prior treatment failure to
  • Montelukast
  • Theophylline
  • Auranofin

52
Baseline Characteristics
  • Weight 64kg
  • IgE -31
  • FEV1 2.49 (74 predicted)
  • VC 3.36 (86)
  • ACQ 3.2/7
  • AQLQ 4.45

53
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54
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55
Admissions
56
XRE Responder Evaluation - RG
1/12 Pre trial
FEV1 1.42L
FENO
QOL
ACQ
IgE
OCS 50mg
Dose 1 21/3/06
0.94L
5.5
2.67
6.14
35
100mg
Dose 2 18/4/06
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 alternate days
Now Nov 06
1.85L




50mg
57
  • Diagnosis is it asthma
  • Risk profile will this person die from disease?
  • Triggers
  • Complications
  • Asthma management skills
  • Treatment
  • ICS/LABA
  • Eos
  • Neut
  • N1 trials

58
Other issues
  • B2 agonist toxicity
  • Genotype
  • Long acting Ach tiotropium
  • High dose b2 formoterol

59
GINA 2006 Asthma treatment steps
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