1 / 82

Bronchial Provocation Testing Sweden October 13 th 2008 45 minutes

Bronchial Provocation Testing Sweden October 13 th 2008 45 minutes. Sandra D Anderson PhD, DSc Department of Respiratory & Sleep Medicine 11 West, Royal Prince Alfred Hospital Sydney NSW AUSTRALIA sandya@med.usyd.edu.au. Conflict of interest.

randall
Download Presentation

Bronchial Provocation Testing Sweden October 13 th 2008 45 minutes

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Bronchial Provocation TestingSweden October 13th 200845 minutes Sandra D Anderson PhD, DSc Department of Respiratory & Sleep Medicine 11 West, Royal Prince Alfred Hospital Sydney NSW AUSTRALIA sandya@med.usyd.edu.au

  2. Conflict of interest • Dr Sandra Anderson is the Inventor on the patents that cover these applications for mannitol • The patent is owned by her employer SSWAHS • The rights to commercialise the intellectual property have been licensed to Pharmaxis Ltd • Dr Anderson purchased her own shares on the open market and holds no options but would receive royalties in the future. • Dr Anderson in her capacity as an employee of RPAH acts as a consultant to Pharmaxis Ltd

  3. Global Initiative for Asthma (GINA) 2007 “Measurements of airway responsiveness. For patients with symptoms consistent with asthma, but normal lung function, measurements of airway responsiveness to direct challenges such as inhaled methacholine or histamine or indirect challenges such inhaled mannitol or exercise challengemay establish a diagnosis of asthma. Measurements of airway responsiveness reflect the “sensitivity” of the airways to factors that can cause asthma symptoms, sometimes called “triggers,” and the test results are usually expressed as the provocative concentration or (dose) of the agonist causing a given fall (20%) in FEV1.” Page 19 Diagnosis and Classification

  4. Why the choice of tests “INDIRECT” “Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract, with or without inducing microvascular leakage. Because the responses to these challenges are modified or even completely inhibited by inhaled steroids, the airway response to these challenges may be a closer reflection of active airway inflammation” Joos GF et al ERS Task Force Eur Respir J 2003: 21:1050-68 “DIRECT” The agonist (usually methacholine) is administered and acts directly on a specific receptor on the bronchial smooth muscle causing it to contract and the airways to narrow. Identifies airway responsiveness consistent with asthma, airway injury, recent virus infection, airflow limitation and airway remodeling.

  5. Bronchial Provocation Tests • Physical ‘Indirect’ • Exercise* • Eucapnic voluntary hyperpnea* (hyperventilation) • Adenosine Monophosphate • Hyperosmolar saline wet aerosol* • Dry Powder Mannitol* • Pharmacological ’Direct’ • Methacholine • Histamine

  6. Mast Cells & eosinophils as source of mediators that cause Bronchial Smooth Muscle to contract Allergen Increase in osmolarity Indirect means the stimulus comes from cells e.g. the mast cell Eosinophils Prostaglandins Leukotrienes Histamine Direct means the agonist acts on the smooth muscle Bronchial smooth muscle

  7. Exercise in the laboratory Exercise in the field, Bronchial Provocation Tests % fall in FEV1 from baseline 10% Exercise & EVH. 15% 4.5% saline & DP mannitol 20% methacholine chloride Eucapnic voluntary hyperpnea 4.5% saline Methacholine aerosol dry powder mannitol *

  8. Methacholine or Histamine • Advantage : • Dose-response curve obtained • Time for testing can be less than exercise • Long safety record but not regulated in many countries • Disadvantages : • Does not predict exercise-induced bronchoconstriction • Negative test does not exclude EIB • Tidal breathing and dosimeter (inhalation to TLC) methods give different PC20 in mild responders. • +ve test may reflect airway injury or recent virus • Rx used to treat EIB has little effect on response

  9. *Airway responsiveness in a normal subject, and in asthmatics with mild, moderate & severe airway hyyperresponsiveness. The response to the agonist is usually expressed as the provocative concentration causing a 20% decline in FEV1 (PC20) 8

  10. Effect of chronic treatment with ICS on response to methacholine demonstrates that airway hyperresponsiveness remains 600 6 400 4 PD20 g PC20 mg/ml 200 2 3200g 0 0 Foresi Jenkins Reddel du Toit Lim Sont Dose (mcg) 1600 1000 1600 800 500 1000 Duration (wks) 64 12 4 104 6 6 Brannan JD et al Clin Resp J 2007 1: 3-8

  11. Leukotrienes (LTD4) & Prostaglandins (PGD2) more potent than histamine/ methacholine 40 PGF2 Methacholine PGD2 Histamine 30 LTD4 20 % Change in FEV1 10 0 10- 5 10-2 10-4 10-3 10-1 100 fold 1000 fold After N Barnes Thorax Concentration (M) O’Byrne Chest 1997; 111:27S-34S

  12. Airway Responsiveness to histamine in those with and without EIB EXERCISE HISTAMINE n+ve-ve Fall in FEV1 >15% 27 77% 33% Fall in FEV1 10-14.9% 50 22% 78% Fall in FEV1<10% 387 12% 88% Backer V. & Ulrik CS. 1992. Clin Exp Allergy 22:741-7 Fall in FEV1 >15% 40 55% 45% Fall in FEV1 <10% 161 12% 88% Haby et al. 1995 Eur Respir J 8:729-36 & MSc U Syd

  13. RPAH Database:adults < 50 yrs age % Positive responses to methacholine decline with increasing lung function. When FEV1 >99% Predicted 53 % had a Positive test with Eucapnic voluntary hyperpnea & 28% with methacholine EVH Methacholine 50 50 50 50 n = 314 n = 418 40 40 40 40 30 30 30 30 % of Category with Positive Challenge 20 20 20 20 10 10 10 10 0 0 0 <80 90-99 80-89 <80 100-109 90-99 80-89 >120 110-119 100-109 >120 110-119 % Predicted FEV1 * % Predicted FEV1 Norval J et al. Respirology 2007 ANZSRS ASM

  14. Steps in the response to various challenge tests Respiratory Water Loss from airway surface Mucosal Dehydration Increase in [Na+], [Cl-], [Ca2+], [K+] Increase in osmolarity Exercise / Dry Air Hyperpnea { Airway surface liquid Epithelial Cells Submucosa Hyperosmolar aerosols Presence of Airway inflammation (eosinophils, mast cells) Mediator Release from Inflammatory Cells AMP Bronchial smooth muscle contraction Methacholine

  15. The severity of EIA is the fall in FEV1 after exercise is a clinically relevant marker of asthma control 5 4 < 10% Normal < 25% Mild 3 FEV1 in litres > 25% Moderate 2 > 50% Severe Exercise 1 0 8 14 20 Time in Minutes SD Anderson 1999

  16. The severity of EIA is related to the % sputum eosinophil percentage Duong M, et al. Chest 2008 133(2):404−11.

  17. EIA is important clinically because oxygen saturation falls 100 42 80 Terbutaline PEFR % Pred 39 PCO2 60 36 Placebo 33 40 7.44 100 7.40 PaO2 pH 80 7.36 98 3 0 SaO2 Base Excess 96 -3 n = 9 -6 94 Rest After 2 min Exercise End Exercise Lowest Post Ex Rest After 2 min Exercise End Exercise Lowest Post Ex

  18. Evaluating Exercise-Induced Asthma Measurement : FEV1 Mode of Exercise : Running on treadmill slope 5.5% Index of Intensity : HR 95%* max (220-age)/4 min Ventilation: > 18 times FEV1L >22 better Duration : 6 min children 8 min adults Inspired Air : Dry Air Room temperature Measurement : Pre & Post 0, 3, 6, 10, 15 min Index of Severity : % Fall and % Predicted * superior to 85% Carlsen et al

  19. 30 n = 18 o C) Field Lab (50% RH 21 Maximum % Fall 20 10 0 FEV FEF FVC 1 25-75 Rundell et al Med Sci Sports Ex 2000: 32;309 -16 Field versus Lab Tests for EIA in elite athletes of 23, 18 were normal in lab test Which means….. Only 5 were positive by lab test

  20. The area under/above the FEV1 time curve relates to the action of released mediators 0 -5 End of Exercise Challenge Return to 5% of Pre-Exercise FEV1 -10 AAC0-60min -15 % Change from Pre-Exercise FEV1 -20 -25 Time to Recovery from Max % Fall in Max % Fall FEV1 to within 5% of Pre-Exercise FEV1 in FEV1 -30 0 5 10 15 30 45 60 75 90 Time after Exercise (min) Kemp JP. et al. J Pediatr 1998;133:424-8

  21. Mediators of airway narrowing in EIA • Histamine first mediator released and probably determines the maximum response but it does not sustain the airway response to exercise. • Leukotrienes sustain the airway response that follows exercise responsible for about 50% of response • Prostaglandins also sustain response to exercise

  22. Increased urinary excretion of 9a, 11b– PGF2in asthmatic patients with and without EIB p < 0.05 p < 0.05 100 80 60 9a, 11b– PGF2 ng.mmol-1 creatinine 40 20 0 Before 30 min 90 min O'Sullivan S, et al. Eur Respir J 1998; 12:345-50

  23. Urinary excretion of Prostaglandin D2 metabolite increases in EIB EIB +ve EIB -ve n = 12 180 n = 9 160 140 p<0.05 120 100 9α,11β-PGF2 ng/mmol creatinine 80 60 40 20 0 Baseline Baseline 45 min post exercise 45 min post exercise Haverkamp HC, Dempsey JA, et al. J Appl Physiol 2005;99:1843-52

  24. Mast cell mediator concentration increases in sputum of asthmatics with EIB in response to dry air 40 5 p = 0.016 2000 p = 0.002 p = 0.018 4 30 1500 3 20 CysLT pg/mL Histamine ng/mL 1000 Tryptase ng/mL 2 10 500 1 0 0 0 Baseline Post-exercise Baseline Post-exercise Baseline Post-exercise Hallstrand T et al, Am J Respir Crit Care Med 2005; 172: 679- 86

  25. Treatment goal with steroids is clear for an indirect test i.e. until response is within the normal range 70 70 60 60 50 50 40 40 % Fall in FEV1 % Fall in FEV1 30 30 20 20 10 10 10/14 (71%) 9/14 (64%) 0 0 Pre Post Pre Post 100 mcg/day for 12 weeks 200 mcg/day for 12 weeks FEV1 100 ± 12 % Predicted FEV1 101 ± 10 % Predicted Budesonide Jonasson G, Pediatr Allergy Immunol 2000; 11:120-5.

  26. Some benefit on EIA at 1,2,& 3 wk Rx with different doses of the ICS Ciclesonide in 26 young adults 14-27yr 40 ug 160 ug 320 ug 80 ug * 30 * * * * * * * * * 20 * Mean Max Fall FEV1 % ± 1 SE 10 0 Visit 3 Visit 2 Visit 1 Subbarao PJ et al JACI 2006;117:1008-13 Baseline Exercise performed 12 hr after last dose

  27. Exercise Response following Ciclesonide low (40,80 µg/day) & high dose (160, 320 µg per day) in those with > and < 5 % eosinophils Duong M, et al. Chest 2008 133(2):404 - 11

  28. EXERCISE TESTING the laboratory Advantages: • The real stimulus that produces the symptoms • High positive predictive value for asthma • Likely to be the most common trigger • Appropriate for assessing drug effects Disadvantages: • Choice is usually limited to cycling and running which may not increase ventilation sufficiently. • Exercise needs to be sports specific to achieve required ventilation cycling/running may not have good sensitivity • Inspired air needs to be ‘dry’ and delivered at very high flow rate (> 100 L/min) for an athlete • 8 minutes of vigorous exercise @ 85-95% HRmax in athlete has some safety issues as treadmill speeds required are high • Several personnel required for testing

  29. Equipment • Special Gas mixture $$$ • Demand valve • Two-way valve • Target balloon • Rotameter • Tubing • Ventilation meter • Spirometer *

  30. PROTOCOL for identifying EIB using Eucapnic Voluntary Hyperpnea with dry air Single Stage Protocol: 6 min* at 30 X FEV1 *or at VEmax Inspired Air : Dry Compressed Air with 4.9% CO2 Index of Intensity: VE % Maximum voluntary ventilation VE % Maximum predicted for exercise Measurement : Pre & Post at 1, 3, 5, 10, 15 min Positive Response : 10 % or more Fall in FEV1 preferably at two or more time points Recovery : Spontaneous or Bronchodilator ± O2 Anderson SD et al Br J Sports Med 2001: 35: 344-347 Based on original publications by *Argyros G et al Chest 1996: 109; 1520-1524 and by Phillips JJ et al Am Rev Respir Dis 1985; 131:31-35

  31. The required ventilation can be easily achieved and sustained using eucapnic voluntary hyperpnea in young active adults suspected of having EIB 70 60 50 40 Severe % Fall in FEV1 30 Moderate 20 Mild 10 Normal 0 0% 20% 40% 60% 80% 100% Ventilation as % Maximum Voluntary Ventilation FEV1 x 35

  32. Comparison in athletes between % fall in FEV1 following 6 min of exercise in the field at 2oC and 6 min of EVH at 19.4oC 50 40 30 20 % Fall in FEV1 10 0 n = 22 6 min 6 min EVH Exercise Rundell KR et al. Chest 2004; 125:909-16

  33. ADVANTAGES outweigh the DISADVANTAGES for using EUCAPNIC VOLUNTARY HYPERPNEA • Advantages: • High sensitivity to identify exercise-induced bronchoconstriction (EIB) in elite athletes • Protocol and inspired air conditions can be adjusted to simulate conditions of a specific sport if necessary • e.g. rowing, cross country skiing, cycling • Negative test = low risk of EIB • Mediators involved are the same as for exercise • Equipment less expensive compared with exercise • Disadvantages: • Special gas mixture needed (~5% CO2 21% O2 balance N2) • Expensive to have a commercially prepared gas mixture • Less sensitive when test duration is < 6 minutes yet • 6-minute protocol can provoke a severe response

  34. Commercial pack & equipment for testing with mannitol www.mannitoltest.info Aka Osmohale *

  35. Mode of Action (2) Development of AridolTM Provocation test protocol(dry powder mannitol for inhalation) inhalation of mannitol Increases osmolarity of the airway surface liquid Inflammatory cells release mediators decrease in (FEV1) in people with active airway inflammation • Mannitol • Naturally occurring sugar alcohol • Not absorbed from the GI tract • Commonly used excipient in tablets

  36. Mannitol Provocation test protocol Inhaled agent: Dry powder Mannitol Progressive Protocol: 0, 5, 10, 20, 40, 80, 160, 160, 160 mg Measurements : FEV1 Pre and at 1 min post dose Positive Response: Fall FEV1 ≥ 15.0% Expression of result: PD15 Recovery: Bronchodilator or spontaneous Anderson SD et al AJRCCM 1997;156:758-765, Brannan JD et al, AJRCCM 1998; 158:1120-6 Holzer K et al J Allergy Clin Immunol 2002: 110; 374-380 Holzer K et al AJRCCM 2003; 167:534-537 Anderson SD Brannan JD Clin Rev Allergy Immunol 2003; 24:27-54 Brannan JD Anderson SD et al Respiratory Research 2005; Dec Porsbjerg C …Backer V et al Clin Exp Allergy 2007;37:22-28 & 2008

  37. Sensitivity PD15 to Dry Powder Mannitol 25 Severe Moderate Mild £ £ 155 mg > 35 mg 155mg 20 15 % Fall FEV1 10 Normal 5 0 635 1 10 100 Cumulative dose of mannitol (mg) Anderson & Brannan Clin Rev All Immunol 2003; 24: 27-54

  38. The relationship of PD15 to mannitol with % fall in FEV1 after exercise in asthmatic subjects* 1000 100 PD15Mannitol (mg) rp = - 0.68 p < 0.01 n = 13 10 0 10 20 30 40 50 60 70 % fall in FEV1 to Exercise Brannan et al, AJRCCM 1998;158:1120-6 *Not taking ICS

  39. Sensitivity to mannitol in relation the % fall after exercise in asthmatic subjects* 1000 rp = - 0.86 p < 0.001 n = 11 100 PD15Manitol (mg) 10 1 10 20 30 40 50 60 70 80 % fall FEV1 after exercise *Not taking ICS Munoz P et al J Appl Physiol 2008

  40. Relationship between response to Mannitol and % Fall FEV1 to Eucapnic Hyperpnea in elite Athletes 60 50 40 30 EVH % Fall in FEV1 20 10 0 No PD 0 100 200 300 400 500 600 PD10 to Mannitol Holzer K et al, AJRCCM 2003:167 534-7

  41. Mediator release in Asthmatic Subjects after mannitol 60 100 90 50 80 ng/mmol creatinine 9a, 11b PGF2 ng/mmol creatinine 40 70 60 30 LTE4 50 20 40 - 60 0 + 30 + 60 + 90 - 60 0 + 30 + 60 + 90 Time (min) Time (min) Brannan et al. Eur Respir J 2003; 22 : 491- 496

  42. The inhibiting effect of sodium cromoglycate on urinary excretion of PGD2 in response to inhaled mannitol 100 95 90 85 80 Placebo 75 9a,11b-PGF2 ng.mmol creatinine-1 70 65 40mg SCG 60 55 50 -60 -30 0 30 60 90 Time (min) Brannan JD, Anderson SD et al. Eur Resp J 2006; 27: 944-50

  43. The inhibiting effect of the beta agonist eformoterol on urinary excretion of PGD2 in response to inhaled mannitol 100 Placebo 95 Eformoterol 90 85 80 9a,11b-PGF2 ng.mmol creatinine-1 75 70 65 60 55 50 -60 -30 0 30 60 90 Time (min) Brannan JD, Anderson SD, et al. Eur Resp J 2006; 27: 944-50

  44. 10 10 0 0 - 10 -10 % change from baseline FEV1 - 20 -20 Placebo eformoterol 24mcg -30 - 30 cromoglycate 40mg - 40 -40 Pre Post 0 10 20 30 40 50 60 70 80 90 R R x x Time following mannitol challenge (min) Brannan JD, Gulliksson M et al. Eur Respir J 2006; 27: 944-950

  45. No significant effect of sodium cromoglycate or eformoterol on increase in urinary excretion of Leukotriene after inhaled mannitol 34 Placebo Cromoglycate 32 Eformoterol 30 28 26 LTE4 ng.mmol creatinine-1 24 22 20 18 16 14 -60 -30 0 30 60 90 Time (min) Brannan JD Anderson SD et al Eur Resp J 2006; 27: 944-50

  46. Mannitol Dry Powder • Advantages: • • Available as a convenient and standardised test kit with pre filled dry powder capsules and single use dry powder inhaler device • • Standard operating procedure for dose and delivery • • Approved by regulatory authorities in Europe, Australia and Korea, to be applied for in USA 2008 • • Dose-response curve obtained • • Positive test predicts active asthma and potential for EIB • • Several mediators involved prostaglandins,leukotrienes,histamine. • • Negative test in an asthmatic = good control of asthma • Published data available in elite athletes • Disadvantage: • Sensitivity to identify asthma in winter athletes not yet tested • Some cough during challenge

  47. Mannitol responsiveness in relation to methacholine in adult 18-56 yr (mean 33yr) asthmatics not taking inhaled corticosteroids 635 100 Mannitol PD15 Geomeans PD15 = 119 mg PC20 = 1.36 mg/ml 10 rp = 0.52 p<0.001 1 0.1 1 10 Methacholine PD20 (μmol) Porsbjerg C et al Clin Exp Allergy 2007

  48. The response to adenosine monophosphate and dry powder mannitol in subjects with clinically recognised asthma 1000 100 AMP PC15 (mg/ml) 10 1 r = 0.823, p<0.001 0.1 0.1 0.1 10 100 1000 Mannitol PD15 (mg) Currie G et al Clin Exp Allergy 2003; 33: 783-788

  49. Relationship between exhaled NO and sensitivity to Mannitol 300 100 Exhaled NO (ppb) rp = -0.63 10 p < 0.001 7 10 100 635 >635 AHR to Mannitol (PD15 mg) AHR -ve Porsbjerg C et al Clin Exp Allergy 2007

  50. Relationship between sputum eosinophils & sensitivity to Mannitol 50 rp = -0.52 40 p < 0.05 30 Sputum Eosinophils (%) 20 10 0 10 100 635 >635 AHR to Mannitol (PD15 mg) AHR -ve Porsbjerg C et al Clin Exp Allergy 2007 Figure 4

More Related