L. P. Boulet - The Late Asthmatic Response

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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

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

JACI 1983

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

Early vs late response according to allergen

Boulet et al. 2015 Submitted

Early vs late response according to allergen

Boulet et al. 2015 Submitted

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

Induced airway inflammation according to allergen

Boulet et al. 2015 Submitted

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

Perception of early vs late allergic asthmatic responses

Turcotte & Boulet ARRD 1993

Leigh et al. AJRCCM 2002

Inhibition of allergen-induced responses

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

J Allergy Clin Immunol 2013;132:1045-55

Allergy 2007: 62: 1101–1110

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