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Phenotyping Severe Asthma
in Children
Andrew Bush MD FRCP FRCPCH
Imperial College & Royal Brompton Hospital
a.bush@imperial.ac.uk
Phenotyping Children
 Why do it?
• School age children: principles
• School age children: phenotypes
• Summary and Conclusions
What is a phenotype?
• A phenotype is here defined as a
feature or cluster of features which
differentiates a separate group from a
defined population at a given time
• Some useful action must result!
– Understanding of mechanisms of disease
– Results in a change of treatment
– Helps with monitoring disease
How Phenotype?
• Investigator prejudice
– Eosinophilic, neutrophilic, mixed,
paucicellular
• Self-fulfilling
Self-fulfilling: Infant Wheezing
Phenotypes
• Never (51%)
• Transient (20%)
– Wheeze 0-3, not at age 6
• Persistent (14%)
– Wheeze 0-3 still present
age 6
• Late onset (15%)
– Wheeze after age 3
How Phenotype?
• Investigator prejudice
– Eosinophilic, neutrophilic, mixed,
paucicellular
• Self-fulfilling
• Mathematical techniques
– PCA, latent class analysis
– Systems biology
Data driven: Infant Wheezing
Phenotypes
Atopy: a dichotomous variable?
Patients and Methods
• Birth cohort study age 5
years
– Questionnaire n = 815
– SPT n = 717
– Specific IgE n = 478
Main Results
• CR 26.1%, CRC 12-1%
• Increased risk with greater
sensitisation
• Outcomes
– Current rhinitis (CR)
– Current rhinoconhunctivitis
(CRC)
Allergy 2007; 62: 1379-86
Conclusions
• Atopy is not ‘all-or-none’
Grass IgE and
current rhinitis
Mite IgE and
perennial rhinitis
Grass IgE and
rhinoconjunctivitis
Grass IgE and
seasonal rhinitis
There is a dose effect for specific IgE and atopic manifestations
16S rRNA: The Sterile Airway?
• 5054 16S rRNA from 43
subjects, > 70% bacterial
species
• Bronchial tree NOT sterile–
2000 sequences cm2
sampled
• Proteobacteria more
abundant in asthmatic
children, prevotella in
controls (same as adults)
• There are more bugs in the
lung than the gut!
–
–
Think gastric acid!
The gut is BETTER protected!
PLoS One 2010; 51: e8578
Phenotyping Children
• Why do it?
 School age children: principles
• School age children: phenotypes
• Summary and Conclusions
Inflammometry: not for mild asthma
Mild
Severe
Standard
strategy
Sputum
strategy
Standard
strategy
Sputum
strategy
ERJ 2006; 27: 483-94
New terminology and definitions
Problematic Severe Asthma
NB: is it asthma at all?
NB: is it ‘asthma plus’
Stage 1 assessment
Difficult asthma
•Remediable factors identified
•Therapy adherence addressed
Genuine severe, therapy
resistant asthma
Lancet 2008; 372: 1019-21
Problematic Severe Asthma
• Difficult asthma =
– becomes easier when the basics are got right
(adherence, environment, etc.)
– NOT candidates for novel therapies
• Severe, therapy-resistant asthma =
– treatment still extremely difficult despite getting
the basics right
– Would be potentially suitable for cytokine specific
therapies
‘Difficult’ vs. ‘Severe, Therapy
resistant’ Asthma
• Psycho-social issues re-addressed
– Anecdotally, more likely to ‘open up’
– 74% referrals were after home discussions
• Adherence
• Smoking
• Allergens
Arch Dis Child 2009; 94: 780-4
Inflammatory pattern?
Phenotype Discordance?
Steroid Responsiveness?
What is target lung function (PAL)?
Next Step: FOB
Assess symptoms,
use of rescue medication
Four weeks later: Decision
time


Assess symptoms,
use of rescue medication

Spirometry & reversibility

Spirometry & reversibility

Induced sputum, FeNO

Induced sputum, FeNO

FOB, BAL, biopsy

Develop treatment plan
Intramuscular
triamcinolone

Mucosal and Luminal Cytology
No correlation between the two: which matters?
Lex et al, BlueJ 2006; 174: 1286-91
Stability of Inflammatory
Phenotypes over Time
• Sputum obtained from 40 subjects with severe
asthma, > twice over a one year period
• Age range 8.4-17.6 years
– 17 children (42%) showed a change in phenotype
(between eosinophilic, neutrophilic and mixed)
• What is a real change in phenotype?
• How often should phenotypes be re-assessed?
Fleming L, MD(Res) 2010
Phenotyping Children
• Why do it?
• School children: principles
 School age children: phenotypes
• Summary and Conclusions
RBH Paediatric Severe Asthma:
Demographics (1)
• N=71 (35 male),
group mean age
11.9, range 4.5 - 17-5
• FP equivalent dose
1000 mcg (5003000); n=21, oral
steroids
• Admissions median
2, 0-21 (12
ventilated)
Cladosporidium
Alternaria
Egg
Milk
Peanut
Trees
Aspergilus
HDM
Dog
Cat
Grasses
0
10
20
30
% positive
%positive
SPTs
40
50
60
RBH Paediatric Severe Asthma:
Demographics (2)
• FEV1 = 76% (33125)
• BDR = 14% (12106)
• ACT (25):
– >20, 3%
– 16-19, 25%
– < 15, 72%
Number of subjects
• FeNO50 = 52ppb
(5-171), NR
<25ppb
15
10
5
0
30
40
50
60
70
80
90
100
Post bronchodilator FEV1 (% predicted)
FEV1 % predicted
110
Serum Total IgE
Ineligible
for
Anti IgE
Percent of subjects
(%)
Frequency
40
30
G median 550 iu
G mean 401 iu
20
normal
10
0
16
40
100
Serum
IgE IgE
log serum
251
630
1584 3980
Airway Phenotype
(post-steroids)
• BAL:
–
–
–
–
14/68 eosinophilic
19/68 neutrophilic
11/68 mixed cellularity
24/68 paucicellular
• EBB
–
–
–
–
19/68 eosinophilic
19/68 neutrophilic
17/68 mixed cellularity
13/68 paucicellular
ERJ 2009; 34: 1052-9
ENFUMOSA
SPTs
• 163 severe asthmatics,
158 mild (low dose ICS)
– Median ICS 1773
– One third oral pred
– Median pred 19 mg
• Female preponderance
(4.4:1 vs. 1.6:1 mild)
• Severe asthma (hatched)
– Less atopic
– More PMNLs
Eur Respir J 2003; 22: 470-7
Induced Sputum
Adult and Paediatric Differences?
100
FEV 1/FVC
90
80
c
mwb
Nearly 50% SA now have COPD!
Stronger signal than smoking
70
wb
a
sa
60
7
10
14
21
28
age at review (years)
35
42
Inflammatory pattern?
Phenotype Discordance?
Steroid Responsiveness?
What is target lung function (PAL)?
Next Step: FOB
Assess symptoms,
use of rescue medication
Four weeks later: Decision
time


Assess symptoms,
use of rescue medication

Spirometry & reversibility

Spirometry & reversibility

Induced sputum, FeNO

Induced sputum, FeNO

FOB, BAL, biopsy

Develop treatment plan
Intramuscular
triamcinolone

Discordant Phenotypes
• Individual variability in clinical,
physiological & pathological parameters
Am J Respir Crit Care Med 2008; 178: 218-24
Inflammometry and Treatment?
• Pauci-inflammatory
– Reduce or do not escalate anti-inflammatory therapy
• Persistently eosinophilic
– Omalizumab
– Theophyllines
– Steroid sparing agents (MTX, CyA)
• Neutrophilic
– Macrolides
– Anti-LTB4
– Theophyllines
• Mixed
– ???
Persistent Airflow Limitation
• Post-steroid trial, post acute BDR FEV1
< -1.96 Z-scores
– What dose, route of administration and
duration of steroids
– What dose of bronchodilator?
• No good paediatric evidence
• BUT, no point flogging a dead horse!
CAMP: Accelerated Airway
Obstruction
• MILD ASTHMATICS,
BUT:
– c25% had airway
‘failure to thrive’
– Independent of
treatment (ICS,
nedocromil, placebo)
BlueJ 2004; 170: 234-41
Re-analysis of START trial
• Does early intervention with ICS prevent exacerbations
(initial question)
– Lancet 2003; 361: 1071-6
• Once daily BUD 200mcg (children) or 400mcg (adults) vi
Turbohaler™ vs. lactose placebo
• 7241 patients aged 5-66 years from 32 countries
• 1363/6767 received one course prednisolone
– Placebo, n=818/3368
– BUD, n=545/3399
• What was the effect on ΔFEV1 (new, post hoc question)
Results:
Corticosteroid response
Response
Number (%)
Symptom
(ACT ≥ 20/25 or 50% increase)
Lung Function
(FEV1 ≥ 80% or 15% increase)
23/47 (49%)
FeNO
(FeNO50 < 24)
22/52 (42%)
Sputum
(Eo < 2.5%)
22/42 (52%)
29/52 (56%)
Proposed criteria for corticosteroid
response
• Complete response: normalisation/
improvement in all parameters (symptoms,
FEV1, FeNO, sputum); 8/52 (15%)
• Partial: response in one or more of the
parameters; 36/52 (69%)
• Non: response in none of the parameters;
8/52 (15%)
Other criteria for steroid
response?
• Clinical response; ACT and FEV1 normal
or improved
– 15/50 (30%)
• Inflammatory response; Normal sputum
cytology, or if no sputum available, FeNO
normal
– 26/52 (50%)
Exacerbations vs. Baseline
control
• Exacerbation of Asthma
– Linear decline, then linear
recovery of PEFR
– No increase in variability
– Usually viral
– Usually difficult to prevent
• Loss of Asthma control
– Wide diurnal variability
BUD
– Morning dips
– BDR > 30%
• These are not the same
thing!
Lancet 1999; 353: 364-9
Eosinophilic/Exacerbating
• CAMP: 30% never exacerbated
– N Engl J Med 2000;343:1054–1063
• Genetics different: CD14, CD16
– Am J Respir Crit Care Med. 2006; 173: 617-22
• Specific mucin glycan phenotype (O-secretor)
– Am J Respir Crit Care Med 2011; 183; 189-94
• Eosinophilic, discordant phenotype
Lessons from TENOR
• Previous exacerbation STRONGLY predictive
of future exacerbation
– Independent of asthma control or duration
– Use of controllers
– Allergic triggers
• Also predictive are:
– Allergic triggers – NOT ‘All or none’
– Non-white race
– Poorly controlled asthma (impairment domain)
The exacerbating child:
What actions to take?
• We (as yet) cannot modulate viral infections!
– Are they taking low dose ICS (care with
escalation)?
– Has baseline control been optimised?
– Has baseline lung function been optimised?
– What are their allergic triggers?
– Has allergen exposure been reduced?
– (Has eosinophilic airway inflammation been
controlled?)
Phenotyping Children
• Why do it?
• School age children : principles
• School age children : phenotypes
 Summary and Conclusions
Summary and Conclusions
• Phenotyping has to be useful if it is to be justifiable
– Understanding mechanisms
– Guiding treatment
• Get the basics right first
• Childhood and adult disease differs
• Be sure you are clear what is meant by ‘severe
asthma’ in a given study
• We need international collaborations
We have a long way to go!