Programa Congreso Para Todos XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015.XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015 Presidente: Alfonso Mario Cepeda Sarabia Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai: 2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza Buenos Aires, marzo 14-16, 2015 - http://www.slaai2015.com

1. XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag
Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza
Buenos Aires, marzo 14-16, 2015 - http://www.slaai2015.com
Programa Congreso Para Todos
XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015

2. The Late Asthmatic Response
Louis-Philippe Boulet
MD, FRCPC, FCCP
Institut universitaire de cardiologie et de pneumologie de Québec
Québec, Canada
Buenos-Aires March 2015
Université Laval

3. SYNOPSIS
1. Historical perspective
2. Asthma physiopathology
3. Airway allergen responses : definitions
4. The LAR: perception, mechanisms and significance
5. The LAR and AHR, inflammation
6. The LAR and asthma drugs
6. Conclusions and perspectives
The Late Asthmatic Response

4. 1873: Blackley: exposure to
high-dose grass pollen
1940: Tiffeneau and Pinelli :
description of FEV1
1951: Herxheimer : many patients
reported late symptoms
1962: Burtin describes the early
and late changes in FEV1
Early 1970’s: Pepys, Orie, De Vries
mechanisms of LAR
Late 1970’s: Hargreave, Cockcroft
consequences of LAR
Allergen-induced responses: Historical perspective

5. PAUCIGRANULOCYTOPENIC
NEUTROPHILIC
Neutrophil elastase
Haematoxyline-eosine
May-Giemsa
staining
EOSINOPHILIC
INFLAMMATION AND ASTHMA
MIXED

6. JACI 1983

7. AIRWAY
RESPONSES
to
ALLERGENS
• Early
asthma7c
response
(EAR)
• Late
asthma7c
response
(LAR)
• Allergen-­‐induced
increase
in
airway
hyperresponsiveness
(AHR)
• Allergen-­‐induced
increase
in
(eosinophilic)
airway
inflamma7on
• Airway
remodelling
Mix of pollens

8. EARLY ASTHMATIC
RESPONSE
• Episode of airflow obstruction
beginning at 5-10 min maximal
20-30 min post allergen
• Inhibited by β2 agonists and
to a lesser extent by other
classes of bronchodilators
(e.g. xanthines, anticholinergics)
• Inhibited by single dose of cromolyn or nedocromil before allergen
• Not inhibited by single dose of inhaled corticosteroid (ICS) before
allergen
• Partial inhibition by regular ICS
TIME (h)
0 1 2 3 4 5 6 7
FEV1
(Litres)
2.5
3.0
3.5
4.0
4.5
DILUENT
RAGWEED
INHALATION

9. THE
ALLERGENIC
AIRWAY
RESPONSE
IN
ASTHMA
Magnitude
of
the
physiologic
response
related
to:
-­‐
the
dose
of
allergen
introduced
in
the
airways
-­‐
the
immune
response
of
the
subject
*
-­‐
the
non-­‐allergic
airway
responsiveness
*
Propor7onnal
to
the
skin
test
wheal
diameter
Cockcroft DW, Davis BE, Boulet LP, Deschesnes F, Gauvreau GM, O'Byrne PM, Watson RM.
The links between allergen skin test sensitivity, airway responsiveness and airway response to
allergen. Allergy. 2005;60:56-9.
N. subjects

10. LATE (DUAL) ASTHMATIC
RESPONSE
TIME (h)
0 1 2 3 4 5 6 7
FEV1
(Litres)
1.0
1.5
2.0
2.5
3.0
DILUENT
GRASS
INHALATION
(About 50% of allergic asthmatic subjects)

11. Very low baseline values for PC20 methacholine and large declines
in FEV1 at 20 min after allergen challenge are predictors of a LAR
in asthmatic subjects
Pedro et al. AJRCCM 2000

12. Influence of the type of allergen on EAR vs LAR ratio
Baseline subjects’ characteristics of dual responders according to the
type of allergen inhaled Boulet et al 2015

13. Early vs late response according to allergen
Boulet et al. 2015 Submitted

14. Early vs late response according to allergen
Boulet et al. 2015 Submitted

15. ALLERGEN-INDUCED AHR
• Direct
AHR
(histamine
&
methacholine)
increased
aRer
allergen
exposure
• Indirect
challenges
may
have
greater
changes
(?)
(e.g.
AMP,
exercise)
• Measured
3
to
30
hr
post-­‐allergen
• Correlated
with
both
LAR
and
allergen
induced
sputum
eosinophilia
• May
be
a
surrogate
for
allergen-­‐induced
inflamma7on
• Rou7nely
measured
in
some
protocols
FEV1
(Litres)
2.7
3.7
DAYS
0 1 2 3 4 5 6 7 8 9 10
RAGWEED
Symptoms
10
1.0
HISTAMINE
PC20
(mg/ml)
Smoke
Cold Air
Exercise

16. No Response EAR LAR
BAL
eos
(%)
@ 7 hr
0
10
20
30
ALLERGEN-­‐INDUCED
EOSINOPHILIA
deMonchy,
1985
The
first
study
demonstra7ng
allergen-­‐induced
airway
eosinophilia
and
its
rela7onship
to
the
allergen-­‐
induced
LAR

17. ALLERGEN-INDUCED INFLAMMATION
• Eosinophils
&
metachroma7c
cells
(mast
cells/basophils)
increased
in
sputum
post
allergen
exposure
• Correlated
to
LAR
(as
is
AHR)
• Time
course
similar
to
changes
in
AHR
• Suspected
to
be
causally
related
to
AHR
• However,
recent
studies
with
IL-­‐12
and
an7-­‐IL-­‐5
have
dissociated
eosinophilia
and
AHR
Before 32 hours
%
Eosinophils
0
5
10
15
20
25
Before 32 hours
%
Metachromatic
Cells
0.0
0.2
0.4
0.6
0.8
1.0
Sputum inflammatory cells
Before and after allergen inhalation
n=12
p=0.04
p=0.01
Pin 1992

18. While individuals with isolated EARs developed an
eosinophilic and basophilic airway inflammatory
response, this was much greater in those with LARs
Gauvreau et al. AJRCCM 2000

19. Induced airway inflammation
according to allergen
Boulet et al. 2015 Submitted

20. Mechanisms of allergen-
induced responses in asthma
• Allergen inhalation causes the upregulation of the
interleukin (IL)-5 receptor on bone marrow
eosinophil progenitors1
• This is caused by cysteinyl leukotriene release
following allergen inhalation 2 and increased
production of IL-5 in the bone marrow 3 resulting in
increased production of eosinophils 4
1 Sehmi et al. JCI 1997
2 Parameswaran et al. AJRCCM 2004
3 Wood et al. AJRCCM 1998
4 Dorman et al. AJRCCM 2004

21. Platelet Activation, P-Selectin, and Eosinophil
β1-Integrin Activation in Asthma
Johansson et al. AJRCCM 2012

22. Gizycki MJ, Adelroth E, Rogers AV, O’Byrne PM, Jeffery PK.
Myofibroblast involvement in the allergen-induced late response in
mild atopic asthma. AJRCMB 1997
The study demonstrates that … “migratory cells with a
contractile phenotype appear in greater numbers in the
late response”.
We propose that subjects who
repeatedly develop a late response
have increased numbers of migrating,
contractile cells that may contribute to
formation of the increased bronchial
smooth-muscle mass observed
in fatal asthma.

23. Montelukast Treatment Attenuates the Increase in Myofibroblasts
Following Low-Dose Allergen Challenge.
Kelly M, Chakir J, Vethanayagan D, Boulet LP, Laviolette M, Gauldie
J, O’Byrne PM. CHEST 2006.
Cells identified on ultrastructure in bronchial submucosa after LDAC
challenge before treatment and after 8 weeks of treatment with either
placebo (dashed line) or montelukast (closed lines).

24. Allergens, inflammation &
remodeling… over time
Allergen exposure in sensitized
asthmatic subjects:
- early and late asthmatic responses
- increase in airway responsiveness
- airway eosinophilic response
- airway remodeling response
- chronic airflow obstruction ?
AllergenAllergen--induced airway responsesinduced airway responses
Early and late asthmatic responses
FEV1
But occasional allergen-induced responses have no perceivable persistent effect
Role of frequency and/or magnitude of exposure ?

25. EAR
vs
LAR-­‐DUAL
responses
in
occupa7onal
asthma
• N: 94 HMW, 114 LMW challenges
– HMW: change in PC20 0,78 ± 1,79 DC methacholine
LMW: 1,90 ± 2,12 1,79 DC methacholine (p=0.02)
• HMW : more EARs(< 1h)
• LMW : more late-dual
responses
(2-8h)
%
0
10
20
30
40
50
60
70
80
réaction
immédiate
réaction
retardée
réaction
mixte
réaction
atypique
HPM
BPM
* p < 0,0001

26. Perception of early vs late allergic
asthmatic responses
Turcotte & Boulet ARRD 1993

27. Leigh et al. AJRCCM 2002
Inhibition of allergen-induced responses

28. Predictive value of allergen challenge in clinical drug
development of currently registered and novel asthma-
controlling agents
Boulet et al. Allergy 2007

29. Predictive value of allergen challenge in clinical
drug development of currently registered and
novel asthma-controlling agents

30. J Allergy Clin Immunol 2013;132:1045-55
Allergy 2007: 62: 1101–1110

31. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses.
Gauvreau GM, O'Byrne PM, Boulet LP et al. N Engl J Med. 2014

32. AMG 157 treatment significantly attenuated the early
and late allergen-induced fall in FEV1 at days 42 and
84. * P < 0.05 AMG 157 compared to placebo
Effects of an anti-TSLP antibody on allergen-induced asthmatic responses.
Gauvreau GM, O'Byrne PM, Boulet LP et al. N Engl J Med. 2014

33. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses.
Gauvreau GM, O'Byrne PM, Boulet LP et al. N Engl J Med. 2014

34. CONCLUSIONS
• The
late
asthma7c
response
is
associated
with
an
increase
in
airway
responsiveness
and
inflamma7on
(IL5
dependent
eosinophilic
response)
• These
responses
are
less
perceived
than
early
responses
• They
seem
more
relevant
to
asthma
physiopathology
than
early
asthma7c
responses
• Inhibi7on
of
allergen-­‐induced
LAR
predicts
poten7al
usefulness
of
new
drugs
in
asthma
treatment

35. XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag
Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza
Buenos Aires, marzo 14-16, 2015
http://www.slaai2015.com/comites-del-congreso/
Información Slaai: www.slaai.org
Programa Congreso Para Todos
Conferencias XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología
Sociedad Latinoamericana de Alergia, Asma e Inmunología, SLaai