Transcript Hyperplasia and hypertrophy of Smooth muscle in asthma

Asthma
in
Adults
A/Prof Alan James
Dept Pulmonary Physiology,
Sir Charles Gairdner Hospital
University Western Australia
NHMRC Practitioner Fellow
Photo Sam James - Sydney
Asthma - Definition
“Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular
elements play a role. The chronic inflammation is associated with airway
hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest
tightness, and coughing, particularly at night and in the early morning. These episodes are
usually associated with widespread, but variable, airflow obstruction within the lung that is
often reversible either spontaneously or with treatment.” (Global Initiative for Asthma –
GINA 2008)
Variable symptoms and variable, excessive airway
narrowing.
There is no gold standard for diagnosis.
Asthma - Pathology
B Araujo et al. Eur Respir J 2008;32:61-69
Airway Hyper-responsiveness
Excessive Airway Narrowing
James et al. ARRD 1992;146:895-9
Lung Function Deficit and
Decline in Asthma
Males
James A et al. AJRCCM 2005;171:109
Lung Function and Severity are
Stable from Child to Adult
120
FEV1%predicted
110
100
90
80
70
C
MWB
WB
A
SA
Lung function by classification at recruitment
60
7
10
14
21
28
35
42
age at review (years)
Phelan et al. JACI 2002;109:189-94
Persistent Wheezers at Age 16 Years
have Persistently Abnormal Lung Function
Allergic
sensitisation
Perinatal
influences
Morgan et al. AJRCCM 2005;355:1253
Airway Smooth Muscle
Airway Smooth Muscle Area
Related to Severity, not Duration
n = 312
James et al. ERJ
2009;34:1040-5
James
et al. ERJ 2009
Airway Inflammation and
Remodeling in Preschoolers
Atopic
Atopic
S Saglani et al. AJRCCM 2007;176:858
Inflammation and Remodeling
Eosinophils and Neutrophils
Mast Cells and Mucus Secretion
Excessive Airway Narrowing
Pathophysiology and Treatment
Corticosteroids
Relievers
How Much Treatment ?
Photo Sam James - Sydney
Maintenance Treatment
Asthma Severity
“Emergency Treatment of Asthma”
S. Lazarus NEJM 2010;363:755
Intermittent
Lowest level of SABA as needed
treatment
required to
achieve
patient's best
level of asthma
control
Mild
Moderate
Severe
Low-dose ICS or
other low-intensity
treatment (e.g.
cromolyn, LTRA,
nedocromil and
theophylline)
Low- to
moderatedose ICS and
LABA (or
other extra
treatment)
High-intensity
treatment (highdose ICS and
LABA ± oral
corticosteroids
and/or other extra
treatment)
Taylor DR, et al. Eur Respir J. 2008 Sep;32(3):545-54.
Maintenance Treatment
Asthma Control
"Asthma control" refers to the extent to which the
manifestations of asthma have been reduced or removed by
treatment •Current clinical control (e.g. symptoms, reliever use and clinic
lung function)
•Future risk (e.g. exacerbations and rapid decline in lung function,
side effects of treatment).
Taylor DR, et al. Eur Respir J. 2008 Sep;32(3):545-54.
How Long to Treat ?
Photo Sam James - Sydney
Responses to Treatment
Jenkins et al.
Symptoms
Lung Function
Airway
Responsiveness
Asthma - Response to Treatment
Haahtela et al NEJM 1994; 331: 700-705.
Therapies Fail to Alter the Natural
History of Lung Function in Asthma
• Childhood Analysis
Asthma Management Program*
Sub-group
• >of1000
4-6 years
age were present at age 6-8
60%
lung children
function deficit
at 18 years
years
• Randomised: Budesonide, Nedocromil, Placebo
25%
more6-8
rapid
decline,
not related
asthma severity
• Age
years:
31-35%
had to
FEV/FVC
< LLN,
regardless of treatmentIE
FE
N = 46
= 47
• Age 18 years: 52% had
FEV/FVC <nLLN
Decline FEV1, mls/yr
FEV1 at end, %
predicted
p
14.6 (1.9-27.3)
31.5 (18.2-44.8)
0.03
64 (19)
77 (19)
0.002
Bai et al. Eur Respir J 2007
CAMP Research Group. NEJM 2000;343:1054
Asthma – Persistent, Local
Airway Inflammation
•Long-term treatment required
•Severity generally unchanged
•Localised inflammation
•Withdrawal of treatment often leads to recurrence
•Inflammation present even when symptoms are absent
•Use of induced sputum, eNO, AHR to monitor
What’s New in Asthma?
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Natural History
Role of Inflammation vs Airway Remodelling
Genetics
Monitoring Therapy
Neutrophilic Asthma
Macrolides, Omalizumab (IgE), Mepolizumab (IL-5)
Anti-tumour necrosis factor
Thermoplasty (Steam?)
Phenotyping!
Omalizumab
•Pooled data from seven studies
•Omalizumab added to current therapy, compared with placebo (5
trials) or current therapy alone (2 trials)
•N = 4308 patients (2511 with omalizumab), 93% severe peristent
•Exacerbation rate reduced by 38% (p < 0.0001)
•Emergency visits reduced by 47% (p < 0.0001)
•Effect not related to patient age, gender, baseline IgE, dosing
schedule (2 or 4 weeks)
•More absolute benefit in more severe asthma (lower FEV1)
Bousquet et al. Allergy 2005;60:302
Omalizumab
Trial in Inner-City Children
•Children, adolescents and young adults (n = 419)
•73% with moderate or severe disease
•Omalizumab added to current therapy, 60 weeks
•Outcomes – asthma symptoms
•Days with symptoms decreased by 24% (p < 0.001)
•Exacerbations reduced 49% to 30% of subjects (p < 0.001)
•Reduced use of ICS and LABAs
•Effect greatest in those sensitised and exposed to cockroach or
house dust mite
Busse et al. NEJM 2011;364:1005
Leukotriene Receptor
Antagonists
• Montelukast, zafirlukast, pranlukast - block leukotrienes
(LT) C4, D4, E4
• Onset – 6 hours (oral), maximal effect – days
• Reduce eosinophils in blood
• Less consistent effect on airway inflammation
• Add-on therapy to ICS (less effective than ICS)
• May have a role in acute asthma as add-on therapy
• Zileuton – block LT B4, C4, D4, E4, - Churg-Strauss S.
Treatment of Remodeling
 Thermoplasty
 Pharmacological - ?
Genetics in Asthma
Genome-wide Association
ORMLD 3
Moffat et al. Nature July 2007
Asthma Phenotype
A Population Study: Cases #1 and #2
• “Has a doctor ever told you that you have
asthma?”
Yes
• Wheeze in last 12 months?
Yes
• Symptoms with exercise?
Yes
• Ever smoked cigarettes?
No
• Use asthma medications?
Yes
• FEV1 post b/d > 80%
Yes
• AHR - PC20 < 8umol methacholine Yes
Case #1
Asthma – Case #1
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Age 27
Asthma onset < 5 years of age
Occupation – lawyer in a city practice
Intermittent symptoms well controlled
with ICS plus LABA
• Otherwise well
Case #2
Asthma – Case #2
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Age 65
Asthma onset 45 years of age
Occupation – farmer
Frequent symptoms, partly controlled with
ICS plus LABA
• BMI = 45
• History of reflux, sleep apnoea, diabetes,
hypertension, coronary artery disease...
• Otherwise well
Cluster Analysis
Clinical phenotypes of asthma. A summary of phenotypes
identified using cluster analysis in primary- and secondarycare asthma populations.
Busselton Cluster Phenotypes
Cluster
n
Cluster Variables
Outcome
Variables
Doctor-diagnosed
Asthma (%)
7
Older, good lung function, no AHR, Smoke low, HF
low, asthma very
464
low atopy
low
6
441
Younger females, no AHR, low
eNO, low eosinophils, low atopy
2
226
Females, obese, no AHR, low
atopy
4
391 Males, no AHR, very atopic
5
127 Males, poor lung function, no AHR Smoke high
1
106
High eNO, high eosinophils, low
BHR, high atopy
Smoke low, HF
high, asthma
31.1
3
215
Reduced lung function, all AHR,
moderate atopy
High asthma
40.0
Smoke low,
asthma low
5.4
15.6
17.7
HF
18.2
24.4
Non-eosinophilic asthma: importance
and possible mechanisms
Douwes J et al Thorax 2002;57:643-648
Pathways leading to IL-5 mediated eosinophil inflammation (Acquired)
or IL-8 mediated neutrophil inflammation (Innate) and asthma.
Receptors for triggers (FcRI, FcRII, TLR4, CD14) and transcription
factors (NFAT, API, GATA, NF-{kappa}B) are intermediate steps.
Macrolides in Asthma
Meta-Analysis
“Not enough evidence to recommend as
treatment for asthma.”
(Recheldi et al. Cochrane Data Syst Rev 2005;Issue, 4:CD002997)
‘AMAZES’
Double-blind, randomised, placebocontrolled trial of azithromycin 500mg three
times a week in patients with asthma who
are symptomatic on ICS, or LABA + ICS
Management of Asthma – My way
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Patient’s history of asthma
Consider diagnosis
Assess Severity – in past and more recently
Address patient questions
Educate - treatment in relation to natural history
Consider further investigation – eNO, sputum, AHR
Aim for complete control before reducing
Reassess - 2-4 weeks, 3 months, 6-12 months
- monitor symptoms (ACQ), FEV, other
AMAZES - Criteria
IN
• ACQ > 1.0
- despite adequate therapy
• Variable airflow
- AHR, B/D >12% or 200ml
• Stable for 4 weeks
OUT
FEV1 < 1.3L
• Smokers
• Current Rx macros/ tetras
• Hypersensitivity
• Pregnant
• Other resp. disease
• Emphysema (DLCO<75%)
Photos Sam James - Sydney