L. P. Boulet - The Late Asthmatic Response
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Transcript of L. P. Boulet - The Late Asthmatic Response
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
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
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
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
PAUCIGRANULOCYTOPENIC
NEUTROPHILIC
Neutrophil elastase
Haematoxyline-eosine
May-Giemsa staining
EOSINOPHILIC
INFLAMMATION AND ASTHMA
MIXED
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
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
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
LATE (DUAL) ASTHMATIC RESPONSE
TIME (h)0 1 2 3 4 5 6 7
FEV1
(Litres)
1.0
1.5
2.0
2.5
3.0DILUENT
GRASS
INHALATION
(About 50% of allergic asthmatic subjects)
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
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
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
HISTAMINEPC20
(mg/ml)
SmokeCold AirExercise
No Response EAR LAR
BALeos(%)
@ 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
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
1.0Sputum inflammatory cells Before and after allergen inhalation
n=12 p=0.04
p=0.01
Pin 1992
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
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
Platelet Activation, P-Selectin, and Eosinophil β1-Integrin Activation in Asthma
Johansson et al. AJRCCM 2012
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.
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).
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 ?
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
Predictive value of allergen challenge in clinical drug development of currently registered and novel asthma-
controlling agents
Boulet et al. Allergy 2007
Predictive value of allergen challenge in clinical drug development of currently registered and novel asthma-controlling agents
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
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
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
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
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