- PPT 2013 4AI 27JAN2013 · 2013. 1. 28. · and airway hyperresponsiveness in athletes Asymptomatic-airway-hyperresponsivess--Symptomaticasthma AHR in athletes: a transient phenomenon

13-01-27

1

Methacholine versus Mannitol Challenge in the Evaluation of Asthma

Clinical applications of methacholine and mannitol challenges  

AAAAI San Antonio

February 2013

Louis-Philippe Boulet MD, FRCPC, FCCP Quebec Heart and Lung Institute

Québec City, Canada

Potential conflicts of interest (last 3 years) Support for research projects/studies AllerGen NCE, Altair, Amgen, Asmacure, AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, IRSC, IRSST, Merck, NIOSH (USA), Novartis, Ono Pharma, Pharmaxis, Schering, Wyeth Advisory Boards GlaxoSmithKline, Novartis Travel grants for presentation of scientific work Novartis, Asmacure Support for Continuing Medical Education lectures AstraZeneca, GlaxoSmithKline, Merck, Novartis Support for production of educational material to patients or physicians AstraZeneca, GlaxoSmithKline, Merck Frosst, Boehringer-Ingelheim, Novartis Collaboration with other organisations Adviser for INNESS (Institut national d'excellence en santé et en services sociaux - Quebec National Institute for Excellence in Health and Social Services) Adviser for the Quebec Asthma and COPD Network Member of the Quebec Workmen Compensation Group (CSST) Chair of the Respiratory Guidelines Committee of the Canadian Thoracic Society President of the D&I Committee of the Global Initiative for Asthma (GINA) Laval University Chair in Knowledge Translation, Education and Prevention in Respiratory and Cardiovascular Health Member of the KT (Knowledge Translation) Canada Network

A special thanks to: •  Julie Turmel •  Valérie Bougault •  Catherine Lemière •  Donald W. Cockcroft for providing me slides/data for this presentation

Methacholine vs Mannitol/ Eucapnic Voluntary Hyperpnea •  Direct vs indirect challenges :

methods, specificity and sensitivity •  Influence of asthma medication •  Occupational asthma investigation •  Assessment of AHR in athletes •  Conclusions

Bronchoprovocation tests

Non-selective - Direct: methacholine, histamine - Indirect: Exercise, EVH, AMP, Mannitol

Selective

- Immunologic : allergen, LMW agents - Nonimmunologic: NSAID/ASA, Sulfites…

DIRECT  STIMULI  

•  Act  directly  on  smooth  muscle  receptors  •  Muscarinic  agonists,  histamine,  LTs,  PGs  •  Response  reflects  smooth  muscle  funcCon  including  airway  calibre  (remodeling)  

•  InflammaCon  affects  smooth  muscle    •  Low  dose  needed  for  bronchoconstricCon    •  Highly  sensi%ve  (with  a  few  excepCons)    

13-01-27

2

INDIRECT  STIMULI  •  Act  indirectly  to  induce  bronchoconstricCon  •  Many  act  through  mediator  release  from  inflammatory  cells  (Exercise  AMP,  EVH,    hypertonic  saline,  mannitol)  

•  Reflect  airway  inflammaCon  •  Smooth  muscle  funcCon  less  important  •  High  dose  usually  needed  to  induce  bronchoconstricCon  

•  Highly  specific  

                                                                 DIRECT            INDIRECT  

Muscle  funcCon      ++++                        ++  Airway  calibre                    ++++              0  (?)  InflammaCon                      ++                              ++++  Dose  needed                        low                          high  Dose  limitaCon            no              yes  SensiCvity                                  high                        low  Specificity                              somewhat  low    high  DiagnosCc  use                  rule  out          rule  in/EIB  

Bronchoprovocation tests

(PC20  in  mg/ml)    PC20                >  16          normal  PC20          4-‐16        borderline  PC20            1-‐4          mild  AHR  PC20      0.25–1        mod  AHR  PC20    <  0.25        severe  AHR    

Methacholine  cut-‐points  (ATS  2000)  Histamine  &  methacholine  

cutpoint  iniCally  selected    

at  8  mg/ml  to  idenCfy  all  asthmaCcs    now  8  ±  one    concentraCon.  So,  4-‐16  is  borderline  

AHR  //  ASTHMA  SEVERITY  

HISTAMINE PC20

8 4 2 1

%

30

40

50

60

70

80

90

100 POSITIVEPREDICTIVE

VALUE

SENSITIVITY

Cockcroft 1992

 PC  20  =  8  or  16  mg/ml  SensiCvity:  Very  high    Specificity:  Fair  NPV:    Very  high  PPV  •      Low  in  random  pop                •    ↑  if  ↑  pretest  prob                •    ↑  if  mch  mimics  Sx                •    ↑  if  PC20  lower                        (eg  PC20  =  1  mg/ml)  

SENSITIVITY

SENSITIVITY AND SPECIFICITY OF METHACHOLINE CHALLENGE

13-01-27

3

METHACHOLINE  

•  A  non-‐nega%ve  methacholine  test  (PC20  <  16  mg/ml)  is  consistent  with  but  not  diagnos%c  of  asthma  

•  DiagnosCc  value  (PPV)  increased  if:      •      PC20  lower  (eg  <  1  mg/ml)      •      Higher  pretest  probability      •      Methacholine  induced  Sx  mimic          natural  Sx  (??)  

METHACHOLINE  

•  A  nega%ve  methacholine  challenge  (PC20  >  16mg/ml)  excludes  current  asthma  with  reasonable  certainty  

•  Several  important  caveats:      •    Symptoms  must  be  clinically  current      •    No  deep  inhalaCons  during  test      •    AbenCon  to  medicaCon  withhold      •    High  intensity  athletes  with  EIB                    may  have  a  negaCve  MCT  

ATS  1999  GUIDELINES  (2000)            Tidal  Breathing  •  2  min  Cdal  breathing  •  Neb  @  0.13  mL/min  •  90  µL  per  dose  

           Dosimeter  •  5  Breaths  B-‐hold  (@TLC)  •  9  µL  per  breath  •  45  µL  per  dose  

Both:    §     ConcentraCons                (0.03-‐32  mg/mL)  §     Timing  between  doses            (5  min)  §     Timing  of  FEV1                              (30  &  90  sec)  §     CalculaCon  of  PC20  

Method

Tidal Breathing Dosimeter

Met

hach

oline

PC 2

0 (m

g/mL

)

0.1

0.3

0.5

1.0

2.0

4.0

8.0

16.0

32.0

64.0

128.0

256.0

n = 55

Methods Comparison 55 subjects

from 3 studies

Cockcroft JACI 2006

Determinants  of  AHR  to  methacholine  

•  Methacholine  AHR  has  possibly  two  components,  fixed  and  variable  component    

•  The  fixed  component  relates  to  airway  remodeling  and  reflects  chronicity    

•  The  variable  component  relates  to  airway  inflamma%on  and  therefore  reflects  disease  acCvity    

•  The  variable  component  may  be  the  only  AHR  early  in  the  course  of  the  disease  

METHACHOLINE  AHR  

•  AHR  ↑  with  inflammatory  sCmuli  (allergen)  •  AHR  ↓  with  anC-‐inflammatory  Rx  (ICS)  •  AHR  modest  correlaCon  with  airway  eos  •  AHR  ↑  with  (non  asthmaCc)  airway  obstrucCon,  likely  a  geometric  issue  

•  AHR  shows  a  modest  correlaCon  with  asthma  severity  

•  AHR  can  be  used  to  monitor  Rx  

13-01-27

4

INDIRECT  AHR  

•  AHR  ↑  more  with  inflammatory  sCmuli    •  AHR  ↓  more  with  anC-‐inflammatory  Rx    •  AHR  beber  correlaCon  with  airway  eos  •  AHR  no  Δ  with  (non  asthmaCc)  airway            obstrucCon  •  AHR  shows  a  beber  correlaCon  with  asthma  severity  /  asthma  acCvity  

•  AHR  beber  to  use  to  monitor  Rx  

Meth  PC20  

AMP  PC20  

p=-‐0.29  

p=-‐0.49  

AHR  &  INFLAMMATION  

n=120  

Small  correlaCon    with  methacholine      

Beber  correlaCon  with  inderect    

(AMP)            

Van  den  Berge  2001  

AHR  ↑  WITH  ↓  FEV1  

Histamine PC20 (mg/ml)

FEV 1

(% p

redi

cted

)

0

10

20

30

40

50

60

70

80

90

100

110ASTHMA

BRONCHITISANDEMPHYSEMA

Verma 1988

0.1 1.0 10

Mannitol was more closely associated with asthma severity in terms of respiratory function and airway inflammation

than methacholine challenge

Effects of medications on methacholine challenge

MedicaRon   Minimum  Rme  Interval  from  last  dose  to  study  

Short  acCng  beta  agonists   8h  

Ipratropium   24h  

Long  acCng  beta2  agonists   48h    

Tiotropium   1  week(?)  

Theophylline   Intermediate  acCng:  24h,  long  acCng:  48h  

Cromolyn  sodium   8h  

Nedocromil   48h  

Hydroxazine,  ceCrizine   3  days  

Leukotriene  modifiers   24h  

The authors do not recommend routinely withholding oral or inhaled corticosteroids, but their antiinflammatory effect may decrease bronchial responsiveness. Inhaled corticosteroids may need to be withheld depending on the question being asked. ATS,  1999  

Airway  hyperresponsiveness,  inflammaCon,  and  subepithelial  collagen  deposiCon  in  recently  diagnosed  versus  long-‐standing  

mild  asthma.  Influence  of  inhaled  corRcosteroids    

Boulet LP, et al. Am J Respir Crit Care Med. 2000 Oct;162(4 Pt 1):1308-13.

13-01-27

5

Asthma and ICS – Phase III trial results

SensiCvity  to  inhaled  steroid  in  treated  asthmaCcs  -‐  56%  of  asthmaCcs  (204/363)  using  ICS  were    posiCve  to  mannitol  when  the  last  dose  was  the  day  before    

Well  controlled  asthmaCc.    Consider  reducing  dosage  of  ICS  

Consider  alternaCve  diagnosis  

Maintain  or  increase  ICS  dosage  

AsthmaCc  with  acCve  airway  inflammaCon  that  will  respond  to  ICS  

Clinical  diagnosis  of  asthma  N=487  

Using  ICS  N=159  Not  on  ICS  N=37  Using  ICS  N=204  Not  on  ICS  N=  87  

Mannitol  NegaCve  Mannitol  PosiCve*  

*  PD15  =  15%  fall  in  FEV1  to  a  dose  ≤  635  mg  

Am J Respir Crit Care Med 2001; 163: 409-12

•  Aim: To determine the predictive factors for failed reduction of ICS in 50 subjects with well controlled asthma

•  50 subjects well controlled asthma, median does of ICS: 1000 mcg BDP. ICS halved every 8 weeks. Histamine, mannitol challenge, spirometry, exhaled NO and, induced sputum at baseline.

•  Monthly visits to establish asthma stability, perform mannitol challenge, spirometry, eNO, sputum

•  Study end points: asthma exacerbation; no ICS treatment for two months •  39 subjects with asthma exacerbation

42

p=0.039  

months  

100%  

50%  

6

ICS  (µg)   520.2  

322.2  

168.8  

0

Leuppi  J  et  al  2001,  AJRCCM  163:406-‐12  

Kaplan-‐Meier  curve:  AHR  to  both  histamine  &  to  mannitol  at  baseline  (solid  line)  beber  predicts  a  failure  to  halve  steroid  dose  than  AHR  to  only  one  test  (dashed  line)        

The odds ratio was 4.38 (1.03 –18.56) p0.5 from baseline

Mannitol group •  ICS increased until PD10 ≥ 635 mg.

13-01-27

6

No difference in mannitol group over standard practice for the time to first

exacerbation

27% less mild asthma exacerbation with the mannitol strategy compared to the control group. No difference in severe asthma

exacerbations. Higher doses of ICS in the mannitol group

Lipworth,  Chest  2012  

ICS dose titration with methacholine vs standard strategy, less mild asthma exacerbations, higher dose of ICS

Sont  et  al,  AmJ  Respir  Crit  care  Med  1999  

ICS  CtraCon  (Sont  et  al.  1999)  

Month of Follow-up

0 3 6 9 12 15 18 21 24

First AsthmaExacerbation

(Cummulative %)

0

25

50

75

Reference-strategy

AHR-strategy

Sont (1999)

AHR  TO  MONITOR  Rx  

ICS  CtraCon  (Sont  et  al.  1999)  

1.  No  requirement  of  ICS  2.  Low-‐dose  ICS  (400mcg  budesonide)  3.  Intermediate  dose  of  ICS  (800mcg)  4.  High  dose  ICS  1600  mcg  +  short  course  of  prednisone  

Sont  et  al,  AmJ  Respir  Crit  care  Med  1999  

Assessment of asthma-related impairement in subjects with occupational asthma

•  30 workers diagnosed with occupational asthma by specific inhalation challenges six years ago.

•  Assessment of AHR by both methacholine and mannitol challenge

Lemiere  et  al  JACI  2011  

13-01-27

7

Mannitol was more closely associated with asthma severity in terms of respiratory function and airway inflammation

than methacholine challenge

In subjects in whom asthma-related disability needs to be assessed, mannitol may provide a better estimation than methacholine challenge.

Prevalence of AHR and asthma in athletes

0 10 20 30 40 50 60 70 80

Controls Dry Cold Humid Mixed

(n = 50 ) (n = 25 ) (n = 25 ) (n = 25 ) (n = 25 )

Asthma diagnosis

% Langdeau et al. AJRCCM 2000; Can Respir J 2004; Eur J Appl Physiol 2000

Swimmers:

7.3 mg/ml

Skiers:

15.8 mg/ml

AHR

Airway hyperresponsiveness is more prevalent in asymptomatic skiers

Sue-Chu et al,Br J Sports Med 2010;44:827–832.

Eucapnic voluntary hyperventilation vs MC Challenge

Methacholine challenge

100

0

20

40

60

80

Swim

mer

s (%

)

IOC-MC

≤ 8 mg/ml ≤ 16 mg/ml ≤ 4 mg/ml

n=7

n=9

n=15

Percentage of swimmers with AHR according to the threshold

chosen

0

20

40

60

80

100

Percentage of swimmers with a positive EVH test

Swim

mer

s (%

)

≥ 10% ≤ 10%

IOC-MC

EVH

Bougault et al. 2010

(n =45)

Correlations between log PC20 and EVH fall in FEV1 with the number of training hours per week in a swimming pool

Training (hours per week)

r = 0.50 (p= 0.02)

0

0,5

1

1,5

2

2,5

10 15 20 25 30

Log

PC20

r = 0.53 (p= 0.02)

0

5

10

15

20

25

30

10 15 20 25 30

EVH

FEV

1 fal

l (%

)

Training (hours per week)

Bougault et al. ERJ 2009

Airway Responses to Eucapnic Hyperpnea, Exercise, and Methacholine in Elite Swimmers.

PEDERSEN, L., S. WINTHER, V. BACKER, S. D. ANDERSON, and K. R. LARSEN. Med. Sci. Sports Exerc., Vol. 40, No. 9, pp. 1567–1572, 2008.

13-01-27

8

Hyperventilation  with  airways  heat  and  water  loss,  increased  penetration  of  pollutants  and  allergens  

Epithelial  ‘damage’  with  loss  of  protective  mediators,  microvascular  leak/plasma  exsudation    

and  trigger  of  a  repair  process    

Changes  of  contractile  properties  of  the  airway  smooth  muscle,  airway  remodelling  ±  Inflammation  

Possible mechanisms of development of asthma and airway hyperresponsiveness in athletes

Asymptomatic  airway  hyperresponsivess    

Symptomatic  asthma  

AHR in athletes: a transient phenomenon ?

Bougault et al. 2010

Effect of continuing or finishing high-level sports on airway inflammation, bronchial hyperresponsiveness, and asthma:

A 5-year p follow-up study of 42 highly trained swimmers

Histamine responsiveness

Helenius I. J Allergy Clin Immunol. 2002;109:962-8.

Conclusions

•  Asthma medications affect the results of both methacholine and mannitol challenges.

•  The AHR to mannitol is predictive of the occurrence of asthma exacerbations when ICS dose is further reduced.

•  AHR to both methacholine and mannitol may be helpful for titrating the dose of ICS.

•  Mannitol seems more associated with the activity of asthma than methacholine.