1. December 6, 2012 Adult Bronchoprovocation Tests Lanny J. Rosenwasser, M.D. Dee Lyons/Missouri Endowed Chair in Immunology Research Professor of Pediatrics Allergy-Immunology Division Childrens Mercy Hospital Kansas City, Missouri Professor of Pediatrics, Medicine and Basic Science University of Missouri Kansas City School of Medicine

2. Working Definition of Asthma Asthma is a disorder of the airways with the following pathophysiological characteristics Chronic inflammation Chronic inflammation Variable airflow obstruction Variable airflow obstruction Hyperresponsiveness to a variety of “triggers” Hyperresponsiveness to a variety of “triggers”

3. “ Twitchy” Airways Bronchial hyperresponsiveness is: An abnormal increase in airflow limitation following An abnormal increase in airflow limitation following exposure to a stimulus; Alternatively, a threshold response (e.g.,  20% fall in FEV1) which occurs at a lower point (dose) than in a healthy individual.

4. Types of Stimuli Direct Stimulus Direct Stimulus Cause airflow limitation by a direct action Cause airflow limitation by a direct action on effector cells (e.g., airway smooth muscle on effector cells (e.g., airway smooth muscle cells, mucus producing cells). cells, mucus producing cells). Indirect Stimulus Indirect Stimulus Cause airflow limitation by an action of cells other than effector cells, which then interact with the effector cells.

5. Direct stimulus Effector cells Airway smooth muscle cells Airway smooth muscle cells Bronchial endothelial cells Bronchial endothelial cells Mucus producing cells Mucus producing cells Airflow limitation Indirect stimulus Intermediary cells Inflammatory cells Inflammatory cells Neuronal cells Neuronal cells

6. Direct Stimuli Acetycholine Acetycholine Methacholine Methacholine Carbachol Carbachol Histamine Histamine Prostaglandin D 2 Prostaglandin D 2 Leukotrienes Leukotrienes Indirect Stimuli Adenosine Adenosine Bradykinin Bradykinin Metabisulfite / SO 2 Metabisulfite / SO 2 Exercise Exercise Hyper/hypotonic aerosol Hyper/hypotonic aerosol Isocap. hyperventilation Isocap. hyperventilation Mannitol Mannitol Propanolol (  -blockers) Propanolol (  -blockers)

7. What do most people use to evaluate airway hyperreactivity? ?

8. Scott GC, Braun SR. Chest 1991;100:322-328. Questionnaire to prominent and active Questionnaire to prominent and active investigators using bronchial provocation techniques. 44 of 94 responses 44 of 94 responses Methacholine (63%) Methacholine (63%) Histamine (17%) Histamine (17%) Exercise (8%) Exercise (8%) Specific antigens (5%) Specific antigens (5%)

9. Direct Stimuli Methacholine Most widely used Most widely used Well standardized Well standardized Easy to obtain today Easy to obtain today Better differentiates reactive/nonreactive airways Better differentiates reactive/nonreactive airwaysHistamine Good correlation with methacholine Good correlation with methacholine More side effects More side effects Development of tachyphylaxis Development of tachyphylaxis

10. Exercise-inducedBronchoconstriction(EIB)Exercise-inducedAsthma(EIA)

11. Exercise needs to be continuous Exercise needs to be continuous Type of exercise matters Type of exercise matters Intensity: 60-80% max causes greatest severity Intensity: 60-80% max causes greatest severity Duration Duration Air temperature and humidity Air temperature and humidity EIB Factors

12. Specific Antigen Performed when proof of sensitivity, Performed when proof of sensitivity, avoidance, or immunotherapy required Most commonly used in research Most commonly used in research Immediate and late responses Immediate and late responses Strong and lasting responses Strong and lasting responses

13. Adenosine Adenosine 5’ – monophosphate (AMP) Adenosine 5’ – monophosphate (AMP) Indirect stimulant Indirect stimulant Releases histamine & other mediators from Releases histamine & other mediators from mast cells Action is blocked by antihistamines Action is blocked by antihistamines May reflect extent of airway inflammation May reflect extent of airway inflammation better than methacholine

14. Adenosine Inhalation of aerosol Inhalation of aerosol Diluent usually 0.9% saline Diluent usually 0.9% saline Dosing scheme range 0.04 to 320 mg/mL Dosing scheme range 0.04 to 320 mg/mL Quadrupling doses reported to be safe Quadrupling doses reported to be safe and efficient - DeMeer et al., Thorax 2001;56:362-365

15. Mannitol Indirect stimulant Indirect stimulant Dry powder Dry powder Osmotic stimulant Osmotic stimulant ( osmolarity of airway surface liquid) Special dry-powder inhalers needed Special dry-powder inhalers needed Procedure not well standardized Procedure not well standardized Reports are mainly from Australia Reports are mainly from Australia

16. Oral Challenges Performed when proof of sensitivity needed Performed when proof of sensitivity needed Common agents and prevalence Common agents and prevalence Metabisulfite: 5 – 10% in adults Metabisulfite: 5 – 10% in adults Tartrazine: <5% Tartrazine: <5% ASA: 4 to 20% ASA: 4 to 20% Time for reaction varies Time for reaction varies

17. Occupational Challenges Specific challenges considered the gold Specific challenges considered the gold standard for dx of occupational asthma Agents Agents Natural organic (flour, wood dust) Natural organic (flour, wood dust) Pharmaceuticals (cimetidine) Pharmaceuticals (cimetidine) Organic chemicals (isocyanates) Organic chemicals (isocyanates) Inorganic chemicals (nickel salts) Inorganic chemicals (nickel salts) Immediate and late responses Immediate and late responses Need for controls (placebo) Need for controls (placebo)

21. Methacholine Challenge BaselinePlacebo 0.07 mg/mL 0.15 mg/mL 0.31 mg/mL Bronchodilator FEV1 (L) 3.15 3.15 3.14 3.14 2.96 2.96 2.75 2.75 2.16 2.16 3.60 3.60 % Change --- --- - 6 - 6 - 12 - 12 - 31 - 31

23. Contraindications Absolute Severe airflow limitation (FEV 1 <50% pred., or < 1.0 L) Heart attack or stroke in last 3 months Uncontrolled hypertension Known aortic aneurysm Relative Moderate airflow limitation (FEV 1 <60% pred., or < 1.5 L) Inability to perform acceptable spirometry Pregnancy Nursing mothers

24. Martin, Wanger, Irvin, et al. Chest 1997;112:53-56 Safety of a Low Starting FEV 1 88 patients with FEV 1 <60% predicted (22% - 59%) 88 patients with FEV 1 <60% predicted (22% - 59%) Mean baseline FEV 1 1.39  0.28 L (0.64 – 2.4 L) Mean baseline FEV 1 1.39  0.28 L (0.64 – 2.4 L) Testing was safe and successful Testing was safe and successful 84 patient’s FEV 1 returned to 90% of baseline, 84 patient’s FEV 1 returned to 90% of baseline, and 4 required a 2 nd treatment

25. Patient Preparation Withhold medications that will interfere Withhold medications that will interfere Explain the test, but don’t over do it Explain the test, but don’t over do it They aren’t going to have an asthma attack!! They aren’t going to have an asthma attack!! Avoid the impact of suggestion. Avoid the impact of suggestion. Consent form Consent form Pre-test questionnaire Pre-test questionnaire Withhold coffee, tea, cola drinks, chocolate Withhold coffee, tea, cola drinks, chocolate for day of study

26. Medication Withholding Schedule Short-acting inhaled bronchodilators8 hrs Med.-acting bronchodilators (e.g., ipratropium) 24 hrs Long-acting bronchodilators48 hrs Oral bronchodilators12-48 hrs Cromolyn sodium8 hrs Nedocromil48 hrs Leukotriene modifiers24 hrs

27. Technical Factors and Aerosols Nebulizer output Aerosol particle size Tubing Lung volume Inspiratory flow rate Breathhold time

28. Dosing Protocols Canadian Protocol (mg/ml) 16 8 4 2 1 0.5 0.25 0.125 0.06 0.03 Diluent Chai, et al. (mg/ml) 25 10 5 2.5 1.25 0.625 0.31 0.15 0.07 Diluent Provoch. Package (mg/ml) 25 10 2.5 0.25 0.025 Diluent Chatham, et al. (mg/ml) 4 br-25 1 br-25 4 br-5 1 br-5 Diluent Corrao, et al. (mg/ml) 4 br-25 1 br-25

29. Dosing Protocols Canadian Protocol (mg/ml) 16 8 4 2 1 0.5 0.25 0.125 0.06 0.03 Diluent Chai, et al. (mg/ml) 25 10 5 2.5 1.25 0.625 0.31 0.15 0.07 Diluent Provoch. Package (mg/ml) 25 10 2.5 0.25 0.025 Diluent Chatham, et al. (mg/ml) 4 br-25 1 br-25 4 br-5 1 br-5 Diluent Corrao, et al. (mg/ml) 4 br-25 1 br-25 ATS 1999 (mg/ml) 16 4 1 0.25 0.0625 Diluent

30. Spirometry Change in FEV 1 is the primary outcome measure Change in FEV 1 is the primary outcome measure Spirometry should meet ATS guidelines for acceptability Spirometry should meet ATS guidelines for acceptability The quality of the spirogram should be examined after The quality of the spirogram should be examined after each maneuver Full FVC efforts lasting > 6 sec should be performed at Full FVC efforts lasting > 6 sec should be performed at baseline and after diluent baseline and after diluent If the FEV 1 is the only outcome measure, the expiratory If the FEV 1 is the only outcome measure, the expiratory maneuver can be shortened to about 2 sec at other maneuver can be shortened to about 2 sec at other stages stages If shortened maneuver is used, assure If shortened maneuver is used, assure inspiration is complete

31. Calculation of Percent Change % Change = Post-diluent FEV 1 - Post-methacholine FEV 1 Post-diluent FEV 1

32. Provocative Concentration (PC) The exact concentration that causes a specific fall in a PFT parameter: PC 20 FEV 1 Concentration that causes a 20% fall in FEV 1 PC 40 SG aw Concentration that causes a 40% fall in specific conductance

33. Quality Control Nebulizer output Nebulizer output Verify output initially & after every 20 uses, until an Verify output initially & after every 20 uses, until an appropriate testing schedule is established for lab. Output for 2-min. TB neb. = 0.13 to 0.15 mL/min + 10% Output for 2-min. TB neb. = 0.13 to 0.15 mL/min + 10% Output for DeVilbiss neb. = 0.009 mL/actuation + 10% Output for DeVilbiss neb. = 0.009 mL/actuation + 10% Verify concentrations of solutions Verify concentrations of solutions Verify challenge procedure Verify challenge procedure Keep records of QC procedures Keep records of QC procedures

34. Safety Precautions for Patient Safety Trained staff close enough to respond quickly Trained staff close enough to respond quickly to an emergency Medications to treat bronchospasm must be Medications to treat bronchospasm must be present in testing area A stethoscope, sphygmomanometer, A stethoscope, sphygmomanometer, and pulse oximeter should be available

35. Precautions for Technician Safety Try to minimize technician exposure Try to minimize technician exposure Testing room should have adequate ventilation Testing room should have adequate ventilation (> 2 AC/hr) Use of exhalation filters useful in TB method Use of exhalation filters useful in TB method Those with asthma are at increased risk and Those with asthma are at increased risk and should take extra precautions to minimize their exposure Safety

36. Categorization of Response PC 20 (mg/mL)Interpretation > 16 Normal BHR > 16 Normal BHR 4.0 - 16 Borderline BHR 4.0 - 16 Borderline BHR 1.0 - 4.0 Mild BHR (positive test) 1.0 - 4.0 Mild BHR (positive test) < 1.0 Moderate to severe BHR < 1.0 Moderate to severe BHR