Asthma transition from childhood to
adolescence and adulthood
Adnan Čustović DM MD PhD FRCP
Professor of Paediatric Allergy
Imperial College London, UK
Outline
• Asthma phenotyping to date
• “Phenotype” vs. ”endotype”
• Discovery of subtypes of asthma and atopy using
unbiased statistical learning techniques
– Latent class analysis (LCA)
– Machine learning techniques
• How can we translate this knowledge to the clinic?
• Beyond IgE:
– Can we distinguish “pathologic” from “benign” atopic
sensitisation?
Asthma phenotyping to date
Aetiology/
Triggers
•Extrinsic/Intrinsic asthma
Rackemann 1927
•Occupational asthma
•Exercise-induced asthma
•Aspirin-induced asthma
Patterns of Variable
Airflow Obstruction
Pathology
• Brittle asthma
•Eosinophilic
• The morning dipper
•Non-eosinophilic
•Irreversible asthma
Turner-Warwick 1977
• Types 1 & 2 brittle asthma
Ayres 1998
•No uniformity
•Descriptive
•Focus on a single dimension of the disease
Pavord 1999
Wenzel 1999
Green 2002
Sputum phenotype is highly variable
Not related to FeNO, change in ICS, asthma control, disease severity
Fleming L et al, Thorax 2012;67:675-81
ASTHMA
Allergy
Lung function
Transient
early
wheezing
Persistent
wheezing /
asthma
Response to
asthma
medication
Wheeze, other
symptoms
Late onset
asthma
Exacerbations
Airway
inflammation
Responds to
treatment
Does not
respond to
treatment
Asthma syndrome:
“Phenotype” vs. “Endotype”
• “Asthma”: not a single disease, but an umbrella
diagnosis which comprises multiple diseases with
distinct mechanisms, and environmental and genetic
associates
• “Asthma phenotype”: an observable characteristic which
can be shared between several of these diseases
• “Asthma endotype”: a hypothetical construct which may
have a tangible value in helping us to
– Better understand the underlying pathophysiological mechanisms
of asthma disease-related diseases
– Identify more effective personalised treatment strategies
Custovic et al, Thorax. 2015 ;70(8):799-801.
It is best to abolish the term asthma1
How can we identify the subtypes of the disease?
• “Asthma syndrome”:
– Usually starts early in life
– Symptoms may progress, remit or relapse over time
• Temporal analysis may be crucial for distinguishing
between different diseases under an umbrella
diagnosis of “asthma”
• Population-based birth cohort (which overcomes
recall bias and permits longitudinal phenotyping)
may be the preferred study design for investigating
this type of disease development
1A
plea to abandon asthma as a disease concept. Lancet 2006;368(9537):705
Birth cohorts: Temporal patterns of
answers to a repeated question
Birth
3 years
6 years
Transient Wheezers
Late Onset Wheezers
Persistent Wheezers
Martinez FD et al, NEJM 1995; 332:133-8
“Unbiased approach” to temporal
pattern: Latent Class Analysis (LCA)
Henderson et al, Thorax 2008; 63: 974-80
Wheezing phenotypes identified by
LCA comparable in two birth cohorts
PW 5.8%
IOW 3.2%
LOW 4.9%
ALSPAC
PEW 16.5%
TEW 16.5%
NW 61.1%
PIAMA
PW 3.5%
TEW 16.7%
LOW 1.7%
IOW 3.1%
NW 75.0%
Savenije et al, J Allergy Clin Immunol. 2011;127(6):1505-12.
Do we need more than just the
information on current wheezing?
• Wheeze phenotypes: based on the answers to
single question
– “Has your child had wheezing or whistling in the chest in the past
12 months?”
• Detailed questionnaire data collected
– Answers to most questions not taken into account
• Patterns of symptoms should be more reliable
• “Unbiased approach” using answers to multiple
questions
– Principal Component Analysis (PCA) may test a theory about the
nature of the underlying processes
A Clustering Approach In Multidimensional Data
Syndromes of coexisting symptoms in childhood
Wheeze with
cold air; 0.52
Wheeze after
Exercise; 0.57
Wheeze with dust;
0.46
Wheeze with colds;
0.78
“WHEEZE”
Cough after
exertion; 0.79
Cough with
cold air; 0.71
Cough during
the night; 0.70
Wheeze with dust;
0.46
“COUGH”
6.8%
27%
Frequent
wheeze; 0.65
Wheeze at night;
0.56
Wheeze limiting
Speech; 0.77
Wheeze with
other pets; 0.69
Loose cough;
0.74
Congestion
with colds; 0.70
Congestion
most days; 0.63
“CHEST
CONGESTION”
4.8%
Congestion
without colds; 0.52
Cough with colds;
0.79
Wheeze with cats;
0.75
Wheeze with pollen;
0.46 (0.42)
“WHEEZE WITH
ALLERGENS”
5.4%
Cough during
the day; 0.67
Wheeze with dogs;
0.65
Cough when excited;
0.56
Wheeze with foods;
0.54 (0.41)
Wheeze with wool;
0.66
Wheeze with soap/
spray/detergent; 0.69
Wheeze with fumes;
0.61
Smith JA et al, Am J Respir Crit Care Med 2008, 177: 1358-1363
“WHEEZE WITH
IRRITANTS”
5.8%
Wheeze with
cig. smoke; 0,63
M
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Ast h
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Alle rg y
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Lung function
Airway resistance
(sRaw)
“Wheeze”
“Cough”
“Chest
congestion”
“Wheeze with
allergens”
Quantitative Atopy
Sum of sIgE titres
to inhalant allergens
Interaction
Family history
Maternal asthma
Interaction
“Wheeze with
irritants”
Smith JA et al, Am J Respir Crit Care Med 2008, 177: 1358-1363
Airway Reactivity
Dry air challenge
M
e ste r
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Ast h
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a n d
Alle rg y
d y
St u
How accurate is parental report of
wheezing?
P<0.001
1.20
P=0.001
P=0.97
sRaw
(kPa/s) 1.10
1.00
N=
152
Never
wheezed
36
Unconfirmed
wheeze
87
Confirmed
wheeze
Lowe at al, Arch Dis Child 2004;89:540-3
M
e ste r
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Ast h
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Alle rg y
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Persistent troublesome wheezing (PTW):
High rates of exacerbations and unscheduled health care utilisation
3.2%
13.1%
16.7%
13.7%
53.3%
Latent Class Analysis (LCA)
including information from
health care records:
Persistent Wheeze =
Controlled + Troublesome
Belgrave et al, J Allergy Clin Immunol 2013;132(3):575-583.e12
M
e ste r
c h
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Ast h
ma
a n d
Alle rg y
d y
St u
Cadherin-related family member 3, CDHR3
Susceptibility locus for early-onset asthma with severe exacerbations
Bonnelykke et al, Nat Genet 2014; 46(1): 51–55
Cadherin-related family member 3, CDHR3
Susceptibility locus for persistent troublesome wheeze (PTW)
PTW vs. NW: RRR 4.09 [2.24-7.47]
PTW vs. TEW: RRR 3.46 [1.78-6.72]
PTW vs. LOW: RRR 4.26 [2.20-8.28]
PTW vs. PCW: RRR 3.01 [1.54-5.90]
Asthma vs. controls: 1.21 [0.85-1.71]
Mutation in rs6967330, coding SNP (G→A) that converts residue cysteine to tyrosine at
position 529 (Cys529→Tyr), associated only with persistent troublesome wheezing
Bonnelykke et al, Nat Genet 2014; 46(1): 51–55
Custovic & Belgrave 2015 (unpublished)
PTW susceptibility gene product CDHR3
mediates rhinovirus C binding & replication
Identification of candidate RV-C receptors by
gene expression analysis
Structure modelling of RV-C15 binding to CDHR3 receptor
-CDHR3 mediates RV-C entry into host cells
-rs6967330 mutation could be a risk factor
for RV-C wheezing illnesses
RV-C15 replication in HeLa cells
transfected with CDHR3 cDNA
Bochkov YA et al, PNAS 2015;112:5485-5490
Persistent troublesome wheeze (PTW):
Highly atopic, with much higher sIgE titre among sensitised children
sIgE (sum, mite, cat and dog)
60
50
40
30
20
10
0
NW
TEW
LOW
PCW
PTW
sIgE titre among sensitised children
Belgrave et al, J Allergy Clin Immunol 2013;132(3):575-583.e12
M
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Ast h
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Alle rg y
d y
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Severe treatment resistant asthma:
10
A
ST
R
A
0
10
5
0
A
20
15
ST
R
30
p=0.039
A
40
Food allergens - sum of SPT wheals
D
p=0.013
sum of milk + peanut + egg SPT wheal (mm)
Aeroallergens - sum of SPT wheals
D
sum of cat + dog + HDM + grass SPT wheal (mm)
Large skin test responses to inhalant and food allergens
Sharples et al, Eur Respir J 2012;40(1):264-7
Atopic sensitisation??
•Positive allergen-specific serum IgE
(sIgE>0.35 kUA/L)?
• Positive skin prick test (MWD>3mm)?
Machine-learned
Phenotypes
of Atopy
Hypothesising
with data:
Machine-learned subtypes of atopy
M
e ste r
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Ast h
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Alle rg y
1,053 Children
switch class
d y
St u
Sensitization Class
8 Allergens
P(Sens’n)
in year 1
Sensitized
Age 1
Sensitized
Age 3
Sensitized
Age 5
Sensitized
Age 8
P(Gain)
P (Loose)
Sens’n
Skin Test
Age 1
Skin Test
Age 3
Skin Test
Age 5
Skin Test
Age 8
sIgE
Age 1
sIgE
Age 3
sIgE
Age 5
sIgE
Age 8
3 intervals
Sens’n state
Infer.NET: Framework for running Bayesian
inference in graphical models; Probabilistic
programming; Customised solutions
P(+ skin)
Sens’
P(+ blood)
Sens’
P(+ skin)
Not Sens’
P(+ blood)
Not Sens’
Mite
Cat
Dog
Pollen
Egg
Milk
Mold
Peanut
Machine learning patterns
of allergic sensitisation
Simpson et al, AJRCCM 2010;181(11):1200-6
Atopic sensitisation “stratified”
Unanticipated risk group for asthma discovered
Four
allergic
sensitisation
patterns
‘learned’
from data
Simpson et al, Am J Respir Crit Care Med 2010; 181(11):1200-6
M
e ste r
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Ast h
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Alle rg y
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Atopic sensitisation “stratified”
“Pathologic” and “benign” subtypes of sensitisation
Lazic et al, Allergy 2013; 68(6): 764-70
Results of cluster analyses should not be
extended to clinical practice
• Wheeze and atopy subtypes (clusters / classes /
phenotypes) can be identified only by using
statistical inference on longitudinal data
• Differentiation between different clusters at any
single cross-sectional point is not as yet possible
– Prerequisite to facilitate the applicability of these findings in
clinical practice & for prevention
• Next step: Discovery of biomarkers to help early
identification of such subgroups
– Potentially of practical value for clinicians
Distinguishing “pathologic” from “benign”
Th2-immunity
• Most patients with asthma are sensitized to
aeroallergens, but only a minority of sensitized
individuals are symptomatic
– Suggests the existence of underlying efficient antiinflammatory control mechanisms
• High-dose allergen immunotherapy:
– Clinical improvement occurs in the absence of significant
reductions in specific IgE titres
• What are the control mechanism(s) that attenuate
expression of IgE-associated responsiveness to
aeroallergens in sensitized individuals?
HDM-specific IgG/IgE ratios: A sharp
inverse relationship to wheezing & asthma
sIgG : sIgE ratio
800
**
600
***
400
200
*
Phenotype neg
Phenotype pos
***
***
***
**
***
**
0
RAINE 14y RAINE 14y RAINE 6y RAINE 6y MAAS 11y MAAS 11y MAAS 5y CAS 3y
CAS 5y
(Asthma) (Rhinitis) (Asthma) (Rhinitis) (Wheeze) (Rhinitis) (Wheeze) (Wheeze) (Wheeze)
Holt, Custovic et al, J Allergy Clin Immunol. 2015 Oct 27. doi: 10.1016/j.jaci.2015.08.044.
sIgG-mediated attenuation of skin prick test
reactivity in vivo
A
%IgE+ Subjects
100
IgE+SPT+
IgE+SPT--
80
60
A. Dissociation between sIgE and SPT
observed across all ages/cohorts
-sIgE in the IgE+/SPT+ children higher than in IgE+/SPTE5), but multiple IgE+/SPT- children had sIgE titres within the
20-30kU/L range
40
20
0
RAINE 14y RAINE 14y
(HDM)
(GRASS)
RAINE 6y
(HDM)
RAINE 6y
(GRASS)
MAAS 11y MAAS 11y
(HDM)
(GRASS)
MAAS 5y
(HDM)
CAS 5y
(HDM)
B
***
sIgG : sIgE ratio
1000
800
**
**
600
B. IgE+/SPT- phenotype consistently
associated with higher sIgG:sIgE ratios
*
***
***
**
400
*
200
0
RAINE 14y RAINE 14y RAINE 6y
(HDM)
(GRASS)
(HDM)
RAINE 6y
(GRASS)
MAAS 11y MAAS 11y
(HDM)
C
MAAS 5y
(HDM)
CAS 5y
(HDM)
***
**
60
% Symptomatic
(GRASS)
f
*
40
20
*
***
**
Low frequency of the IgE+/SPT- phenotype amongst severe
asthmatics
0
RAINE 14y RAINE 14y RAINE 6y
HDM
(Asthma)
GRASS
(Rhinitis)
HDM
(Asthma)
RAINE 6y
GRASS
(Rhinitis)
C. Prevalence of asthma and rhinitis
higher amongst the IgE+/SPT+ relative
to IgE+/SPT- children
MAAS 11y MAAS 11y
HDM
(Asthma)
GRASS
(Rhinitis)
MAAS 5y
HDM
(Asthma)
CAS 5y
HDM
(Asthma)
Holt, Custovic et al, J Allergy Clin Immunol. 2015 Oct 27. doi: 10.1016/j.jaci.2015.08.044.
sIgG-mediated attenuation of sIgEdependent basophil activation in vitro
A
B
Holt, Custovic et al, J Allergy Clin Immunol. 2015 Oct 27. doi: 10.1016/j.jaci.2015.08.044.
Allergen-specific Th-memory responses and
sIgE/sIgG “balance”
Gene expression in allergentriggered Th-memory recall
responses
High sIgG:sIgE ratios
associated with reduced
signalling of multiple pathways
(particularly those denoting Th2
immunity/T-cell activation),
coupled with increased IL-10
signalling
Holt, Custovic et al, J Allergy Clin Immunol. 2015 Oct 27. doi: 10.1016/j.jaci.2015.08.044.
Complementary IL-10-dependent pathways
for regulation of allergic inflammation
Acting indirectly
via promotion of
sIgG1
production
which
modulates the
FcR1dependent
acute phase
Acting directly
via modulation of Th2memory cell activation in
the late phase response
Holt, Custovic et al, J Allergy Clin Immunol. 2015 Oct 27. doi: 10.1016/j.jaci.2015.08.044.
Conclusions
• “Asthma”: not a single disease
– An umbrella diagnosis which comprises several diseases
with distinct pathophysiological mechanisms
• Disease subtypes can be identified by using
statistical inference on rich longitudinal data
– Differentiation between different clusters at any single
cross-sectional point not as yet possible
• Challenge:
– Integrate different levels of information to combine high
dimensional clinical, genetic, environmental and biological
data to fully understand different subtypes of asthma
– Identify biomarkers for such disease subtypes
– Identify novel targets for drug discovery to enable
personalized approach to management
Search for the cure for asthma
• Recognition that asthma is not a single disease:
The end of the beginning in the search for the cure
for “asthmas”
• Understanding pathophysiology of diseases under
an umbrella diagnosis of “asthma” will lead to novel
therapeutic target discovery and enable a genuinely
personalized approach to management
• Essential: Iterative interdisciplinary dialogue
between clinicians, statisticians, computer
scientists, geneticists, physicist and basic scientist
• Vision: Cross-disciplinary teams contributing to the
generation of new knowledge (“Team science”)
Belgrave, Simpson & Custovic, Am J Respir Crit Care Med 2014; 189(2):121-3
M
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Prof S Johnston
Prof P Holt
Prof A Simpson
Prof Iain Buchan
Prof F Martinez
Prof AJ Henderson
Prof G Devereux
Dr S Turner
Prof P Cullinan
Dr Emmanuel
Addo Yobo
Prof H Bisgaard and Pis
of EAGLE Birth Cohorts
Consortium
Prof G Roberts
Prof H Arshad
Prof J Holloway
Prof C Bishop
Dr John Wynn
Prof O Kalayci Prof N Aberle
J P MOULTON
CHARITABLE
FOUNDATION
Prof S Ahlstedt
Prof E Melen
Prof M Wickman
Question 1
Which of the following statements are true
regarding asthma phenotypes?
a. The term phenotype relates to underlying
molecular mechanisms
b. Sputum cell count phenotypes are stable in
childhood asthma
c. Blood eosinophilia phenotype predicts steroid
responsiveness
Question 2
Phenotypes in asthma
a. Are defined by patterns of inflammation
b. Aspirin-sensitive asthma manifests in early
childhood
c. Transient early childhood wheeze is associated
with low sensitisation and IgE
Question 3
Stratified medicine in asthma:
a. Is a modern term for guideline-compliant care
b. Is informed by comparisons of group-mean
data from clinical trials
c. Patient characterisation which should be is
used to guide pharmacological and nonpharmacological treatments