Nasal & Bronchial Provocation Test P. Putivoranat, MD. 22/05/09
Bronchial Provocation Test <ul><li>Airway hyperresponsiveness & Measurement </li></ul><ul><li>Non-selective BPT </li></ul...
Bronchoprovocation stimuli Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy : principles and practice...
Non-Selective Bronchial Provocation Test
Metacholine vs Histamine challenges <ul><li>Methacholine : synthetic derivative of A cetylcholine </li></ul><ul><ul...
Contraindications for Metacholine challenge test <ul><li>Absolute : </li></ul><ul><li>Severe airflow limitation (FEV1 < ...
F actors Decrease Bronchial Responsiveness Am J Respir Crit Care Med 2000; 161: 309-29.
F actors Increase Bronchial Responsiveness <ul><li>*Studies of acute effects of smoking on airway hyperreactivity & meth...
Hypothetical methacholine dose–response curves Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
2 Metacholine challenge methods Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practic...
Metacholine challenge test Am J Respir Crit Care Med 2000; 161: 309-29.
C ut points of Methacholine BPT <ul><li>mainly from the tidal breathing method </li></ul><ul><li>1. Normal – PC 20 >16...
P ediatric BPT <ul><li>A ge ≥ 6 yrs . ( perform spirometry ) </li></ul><ul><li>Too young : auscultation, transcut....
Indirect Airway Hyperresponsiveness <ul><li>Exercise </li></ul><ul><li>Hyperventilation : EVH, Standardized Cold air </li...
Mechanism of Indirect Bronchial Challenge Eur Respir J 2003; 21: 1050-68
Methacholine vs. Non-selective Indirect BPT Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy : prin...
Clinical Utility of Non-Selective BPT <ul><li>Diagnosis </li></ul><ul><li>Occupational Asthma </li></ul><ul><li>Drug effec...
Non-Selective BPT for Diagnosis <ul><li>Diagnostic test of Asthma </li></ul><ul><li>Direct BPT : N ormal spirometry p...
Non-Selective BPT for Diagnosis <ul><li>Diagnostic test of Asthma, EIB </li></ul><ul><li>Indirect BPT : highly specif...
FN & FP results for Non-selective BPT Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308. Indirect (...
Selective Bronchial Provocation Test
Allergen BPT <ul><li>Allergen-induced Early Asthmatic Response </li></ul><ul><li>Allergen-induced Late Asthmatic Response ...
Allergen-induced EAR 32% early A sthmatic response <ul><li>M ax . 10 - 20 mins or slightly longer & R esolves spont . 2...
Allergen-induced LAR Late ≥ 40% E arly 33% Dual Asthmatic response <ul><li>4-5 hrs. after Challenge , may persist ≥ ...
Allergen-induced increase in AHR AHR: 2-3 hrs. after Challenge, may persist several days DAR Middleton’s Allergy : prin...
Allergen-induced Eosinophils <ul><li>S putum exam & S aline-induced sputum </li></ul><ul><li>↑ Eosinophils in DAR but ...
Medications inhibit Allergen-induced responses Diamant Z. et al. + 0 + ± <ul><li>Heparin </li></ul>Pepys J et al, Hedardt...
Summary of BPT <ul><li>D irect BPT (e.g. M ethacholine) : h ighly S ensitive & function best to exclude A sthma w...
 
Nasal Provocation Test <ul><li>Indications & Contraindications </li></ul><ul><li>Outcomes of nasal provocation </li></ul>...
Clinical Indications for NPT <ul><li>1. A ssess role of A llergens implicated by p t Hx when Neg skin testing & R ...
Scientific Indications for NPT <ul><li>1. I nvestigate P hysiologic, M orphologic & C ellular of A llergen-induced im...
Contraindications for NPT <ul><li>Absolute </li></ul><ul><li>1. Acute bact. or viral Rhinitis or Sinusitis </li></ul><ul>...
Washout periods for different drugs before NPT Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : princi...
Local delivery systems <ul><li>Syringe </li></ul><ul><li>Dropper </li></ul><ul><li>Pipette, Micropipette </li></ul><ul><li...
Filter paper disc Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
Exposure Chambers <ul><li>Allergens : Pollen, Cat, Dust mite </li></ul><ul><li>Pollutants : ETS, CO 2 </li></ul>Middleto...
Outcomes of NPT <ul><li>Subjectives : Symptoms </li></ul><ul><li>Objectives </li></ul><ul><ul><li>Measurements of Nasal p...
Symptom outcome <ul><li>S neezing, P ruritus, R hinorrhea, P osterior nasal drainage, N asal congestion </li></ul><u...
Nasal Peak Flow <ul><li>Peak Flow Meter </li></ul><ul><li>Nasal Peak Expiratory Flow (NPEF) </li></ul><ul><li>Nasal Peak ...
Rhinomanometry <ul><li>Active vs. Passive </li></ul><ul><li>Anterior vs. Posterior </li></ul><ul><li>Pressure-Flow cur...
Acoustic Rhinometry <ul><li>S ound impulse is directed into single nasal passag e & E choes reflected from nasal walls ...
Nasal Cells & Tissue <ul><li>Blown secretions </li></ul><ul><li>Nasal lavage </li></ul><ul><li>Mucosal imprint </li></ul>...
Nasal Cytology & Tissue Adapted from Ann Allergy Asthma Immunol 2001; 86:355-365. & Middleton’s Allergy : principles a...
Response of Unilateral NPT <ul><li>- MC degranulation : Histamine, Tryptase, LTs & others </li></ul><ul><li>- Histamine ...
Nasal Allergen Provocation Test <ul><li>Guidelines : No International available, some European countries </li></ul><ul><...
Ann Allergy Asthma Immunol 2001; 86:355-365.
Allergen challenge-induced leukocyte influx in nasal lavage fluids Middleton’s Allergy : principles and practice. 7 th e...
Causes of FP & FN NPT results <ul><li>False-Positive Results </li></ul><ul><li>Use of preservatives (e.g., phenol, glycero...
NPT with Physical, Chemical & Biochemical stimuli <ul><li>Physical stimuli </li></ul><ul><li>Neural & Irritant stimuli...
NPT with Physical stimuli <ul><li>Cold air : sensorineural activation & mast cell mediator release, ability to keep na...
NPT with Neural & Irritant stimuli <ul><li>Capsaicin : Vanilloid receptor TRPV1 (on Unmyelinated, slow-conduct sensory...
NPT with Biochemical stimuli <ul><li>Histamine </li></ul><ul><li>Methacholine </li></ul><ul><li>Other mediators of aller...
Unilateral NPT with H istamine & M ethacholine Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-9...
NPT with Neuropeptides <ul><li>Neuropeptides released from : </li></ul><ul><li>Sensory nerve endings (unmyelinated, slo...
NPT with Adenosine 5’-monophosphate (AMP) <ul><li>MC degranulation & sensory n. stimuli </li></ul><ul><li>AMP induce <...
Summary of NPT <ul><li>NPT : Study Pathophysiology of Rhinitis, Pharmacodynamic & Medications against Rhinitic disorders...
QUIZ
<ul><li>W hich of the following stimuli for bronchial provocation challenge testing is independent of mast cell activatio...
<ul><li>W hich of the following bronchoprovocation tests is the best predictor for developing asthma? </li></ul><ul><li>a...
<ul><li>W hich of the following medications inhibits both the early & late phase reaction to inhalation allergen challeng...
<ul><li>NPT is contraindicat ed when the patient ? </li></ul><ul><li>a. has received oral steroid within 40 days </li>...
<ul><li>In w hich of the following conditions does nasal cytology have the greatest diagnostic utility? </li></ul><ul><li...
<ul><li>Indications for the use of NPT in clinical practice include all of the following EXCEPT: </li></ul><ul><li>a. To c...
<ul><li>Which of the following is NOT an absolute contraindication for NPT? </li></ul><ul><li>a. Acute period of allergic ...
<ul><li>Which of these statements is false? </li></ul><ul><li>a. NPT can be done 4 wks after episode of allergic or infect...
<ul><li>A positive NPT is determined by: </li></ul><ul><li>a. The maximum allergen dose that patient received </li></ul><u...
<ul><li>Which of these statements is false? </li></ul><ul><li>a. NPT is a well standardized method and is frequently used ...
Thank you
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Nasal and Bronchial Provocation Tests

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Transcripts - Nasal and Bronchial Provocation Tests

  • 1. Nasal & Bronchial Provocation Test P. Putivoranat, MD. 22/05/09
  • 2. Bronchial Provocation Test <ul><li>Airway hyperresponsiveness & Measurement </li></ul><ul><li>Non-selective BPT </li></ul><ul><ul><li>Direct airway hyperresponsiveness </li></ul></ul><ul><ul><li>Indirect airway hyperresponsiveness </li></ul></ul><ul><ul><li>Clinical utility </li></ul></ul><ul><li>Selective BPT </li></ul><ul><ul><li>Allergen BPT </li></ul></ul><ul><ul><li>Occupational BPT </li></ul></ul><ul><li>Summary </li></ul>
  • 3. Bronchoprovocation stimuli Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308. <ul><li>ASA </li></ul><ul><li>NSAIDs </li></ul><ul><li>Food additives (?) </li></ul><ul><li>Physical : </li></ul><ul><li>Exercise </li></ul><ul><li>EVH </li></ul><ul><li>Cold air </li></ul><ul><li>Non-isotonic aerosols </li></ul><ul><li>Pharmacological : </li></ul><ul><li>AMP </li></ul><ul><li>Propanolol </li></ul><ul><li>Bradykinin </li></ul><ul><li>Mannitol </li></ul>Non-Immunologic Indirect <ul><li>Allergen </li></ul><ul><li>High MW prot-containing </li></ul><ul><li>IgE mediated </li></ul><ul><li>Occupational </li></ul><ul><li>Low MW sensitizer </li></ul><ul><li>Mechanism uncertain </li></ul><ul><li>Histamine </li></ul><ul><li>Metacholine </li></ul><ul><li>Prostaglandins </li></ul><ul><li>Leukotrienes </li></ul>Immunologic Direct Selective Non-selective
  • 4. Non-Selective Bronchial Provocation Test
  • 5. Metacholine vs Histamine challenges <ul><li>Methacholine : synthetic derivative of A cetylcholine </li></ul><ul><ul><li>metabolized more slowly by cholinesterase </li></ul></ul><ul><ul><li>blocked or lessened by atropine or similar anticholinergic agents </li></ul></ul><ul><ul><li>more commonly used & preferred </li></ul></ul><ul><li>H istamine : more systemic side effects ( headache,flushing & hoarseness ) , less reproducible BHR </li></ul><ul><li>Similar mechanism : Direct activating contraction of Bronchial smooth m. after binding to Cholinergic receptors (& H receptor) </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29. Clin Exp Allergy 2004; 34: 9-16.
  • 6. Contraindications for Metacholine challenge test <ul><li>Absolute : </li></ul><ul><li>Severe airflow limitation (FEV1 < 50% predicted or < 1.0 L) </li></ul><ul><li>Heart attack or S troke in last 3 mo </li></ul><ul><li>Uncontrolled hypertension, systolic BP > 200, or diastolic BP > 100 </li></ul><ul><li>Known A ortic aneurysm </li></ul><ul><li>Relative : </li></ul><ul><li>Moderate airflow limitation (FEV1 < 60% predicted or < 1.5 L) </li></ul><ul><li>Inability to perform acceptable-quality spirometry </li></ul><ul><li>Pregnancy </li></ul><ul><li>Nursing mothers </li></ul><ul><li>Current use C holinesterase inh medication (for myasthenia gravis) </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29.
  • 7. F actors Decrease Bronchial Responsiveness Am J Respir Crit Care Med 2000; 161: 309-29.
  • 8. F actors Increase Bronchial Responsiveness <ul><li>*Studies of acute effects of smoking on airway hyperreactivity & methacholine challenge testing are not consistent. </li></ul><ul><li>There is some evidence of a brief acute effect that can be avoided by asking subjects to refrain from smoking for a few hours before testing </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29. Days to months Chemical irritants Uncertain* Cigarette smoke 1 wk Air pollutants 3–6 wk Respiratory infection Months Occupational sensitizers 1–3 wk Exposure to environmental Ag s Duration of Effect Factor
  • 9. Hypothetical methacholine dose–response curves Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 10. 2 Metacholine challenge methods Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308. False Negative
  • 11. Metacholine challenge test Am J Respir Crit Care Med 2000; 161: 309-29.
  • 12. C ut points of Methacholine BPT <ul><li>mainly from the tidal breathing method </li></ul><ul><li>1. Normal – PC 20 >16 mg/m l. </li></ul><ul><li>2. Borderline – PC 20 4 - 16 mg/m l. </li></ul><ul><li>3. Mild AHR – PC 20 1 - 4 mg/m l. </li></ul><ul><li>4. Moderate AHR – PC 20 0.25 - 1 mg/m l. </li></ul><ul><li>5. Marked AHR – PC 20 < 0.25 mg/ ml. </li></ul><ul><li>AHR severity ≠ Asthma severity </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29.
  • 13. P ediatric BPT <ul><li>A ge ≥ 6 yrs . ( perform spirometry ) </li></ul><ul><li>Too young : auscultation, transcut. P tc O 2 , plethysmograph </li></ul><ul><li>Cut point : same as adult </li></ul><ul><li>Metacholine challenge test </li></ul><ul><ul><li>Prefer the Tidal breathing method </li></ul></ul><ul><ul><li>Best sensitivity & specificity : PC 20 3-4 mg/ml. </li></ul></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 14. Indirect Airway Hyperresponsiveness <ul><li>Exercise </li></ul><ul><li>Hyperventilation : EVH, Standardized Cold air </li></ul><ul><li>Non-Isotonic aerosols : Hypertonic saline, Distilled water </li></ul><ul><li>AMP (Adenosine Monophosphate) </li></ul><ul><li>Dry Powder Mannitol </li></ul><ul><li>Other Indirect Challenge : Propanolol, Bradykinins, Tachykinins, SO 2 </li></ul>Clin Exp Allergy 2004; 34: 9-16. Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.
  • 15. Mechanism of Indirect Bronchial Challenge Eur Respir J 2003; 21: 1050-68
  • 16. Methacholine vs. Non-selective Indirect BPT Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308. <ul><li>Europe </li></ul>40 min. 5 min. 30 & 90 sec. PC 20 Adenosine Monophosphate up to 400 mg. Non -Osmotic <ul><li>AMP </li></ul><ul><li>High AHR Sensitivity </li></ul><ul><li>Less Asthma Specific </li></ul>50 min. 5 min. 30 & 90 sec. PC 20 Methacholine 0.03-16 mg/ml Direct <ul><li>Methacholine </li></ul>1 min. 30 & 90 sec. 10-15 min. 10-15 min. min. Measure 2 min. 0.5-8 min. 3 min. 10-15 min. 5 min. Interval <ul><li>Induce Sputum </li></ul><ul><li>Australia </li></ul>PC 20 4.5% NSS Ultrasonic nebulizer Osmotic <ul><li>Non-isotonic aerosols </li></ul><ul><li>Normal: PD 15 > 635 mg </li></ul><ul><li>Less dose limitation   Sensitivity </li></ul>20-25 min. PD 15 Dry powder Mannitol 0-635 mg. Osmotic <ul><li>Mannitol </li></ul><ul><li>Excessive dry airway </li></ul>30 min.  FEV 1 10-15% Exercise 80-90% Max.HR for 6 min. Osmotic <ul><li>Exercise </li></ul><ul><li>Excessive dry airway </li></ul><ul><li>Similar to Exercise </li></ul> 10% FEV 1 Dry air with 5% CO 2 for 6 min. Osmotic <ul><li>Eucapnic Voluntary Hyperpnea </li></ul><ul><li>Excessive dry airway </li></ul>12 min. PD 20 18 º C 0% Humidity Osmotic <ul><li>Cold air </li></ul>Target Mechanism Duration Note Methods
  • 17. Clinical Utility of Non-Selective BPT <ul><li>Diagnosis </li></ul><ul><li>Occupational Asthma </li></ul><ul><li>Drug effects & Treatment monitoring </li></ul><ul><li>Prognosis </li></ul>
  • 18. Non-Selective BPT for Diagnosis <ul><li>Diagnostic test of Asthma </li></ul><ul><li>Direct BPT : N ormal spirometry prior to M ethacholine challenge relates safety & correct interpreta tion </li></ul><ul><li>N on-asthmatic airflow obstruction (e g. COPD) ↑ AHR to direct stimuli & highly correlated with degree of  FEV1 & most likely related to obstruction </li></ul><ul><li>PPV of histamine PC20 < 8 mg/mL in random population was shown to have PPV < 50%  PPV for A sthma Dx will improve with ↑ pretest probability </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 19. Non-Selective BPT for Diagnosis <ul><li>Diagnostic test of Asthma, EIB </li></ul><ul><li>Indirect BPT : highly specific but not very sensitive </li></ul><ul><li>C onfirm Dx of A sthma </li></ul><ul><li>S ubjects might have EIB : challenges should be choice for I nternational athletic agencies, A rmed forces, P olice forces, SCUBA diving </li></ul>Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 20. FN & FP results for Non-selective BPT Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308. Indirect (Exercise, EVH, etc.) Direct (Metacholine) <ul><li>Should be infrequent </li></ul><ul><li>Common in mild or well-controlled asthma </li></ul><ul><li>Medication effects as above </li></ul><ul><li>Normals (5-15%) </li></ul><ul><li>Rhinitis (20-40%) </li></ul><ul><li>Sedentary individuals with subclinical asthma </li></ul><ul><li>Elite or high-intensity athletes </li></ul><ul><li>Medications </li></ul><ul><li>Functional antagonist ( β 2 agonist) </li></ul><ul><li>Specific antagonist (anti-muscarinic) </li></ul><ul><li>Symptoms or exposures not clinically current </li></ul><ul><li>TLC inhalations during challenge </li></ul><ul><li>(Eosinophilic bronchitis) </li></ul>False Positive False Negative
  • 21. Selective Bronchial Provocation Test
  • 22. Allergen BPT <ul><li>Allergen-induced Early Asthmatic Response </li></ul><ul><li>Allergen-induced Late Asthmatic Response </li></ul><ul><li>Allergen-induced increase in AHR </li></ul><ul><li>Allergen-induced Eosinophils </li></ul><ul><li>Standardized Allergen Challenge method </li></ul><ul><li>Other Allergen Challenge methods </li></ul><ul><li>Medications Inhibit Allergen-induced responses </li></ul>
  • 23. Allergen-induced EAR 32% early A sthmatic response <ul><li>M ax . 10 - 20 mins or slightly longer & R esolves spont . 2 - 3 hrs. </li></ul><ul><li>Time - course similar to bronchoconstriction following exercise, but may be slightly more prolonged. </li></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 24. Allergen-induced LAR Late ≥ 40% E arly 33% Dual Asthmatic response <ul><li>4-5 hrs. after Challenge , may persist ≥ 12 hrs. </li></ul><ul><li>IgE mediated & Airway Inflammation </li></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 25. Allergen-induced increase in AHR AHR: 2-3 hrs. after Challenge, may persist several days DAR Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 26. Allergen-induced Eosinophils <ul><li>S putum exam & S aline-induced sputum </li></ul><ul><li>↑ Eosinophils in DAR but not isolated EAR & not in I nterval phase (2–3 hrs) in dual respon se </li></ul><ul><li>↑ A irway respons e in LAR & ↑ E osinophils together and I nh . by C orticosteroids </li></ul><ul><li>Study of A sthma pathogenesis & I nvestigation of new medications </li></ul>Allergy 2006: 61: 111–8 . Placebo Grass pollens Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
  • 27. Medications inhibit Allergen-induced responses Diamant Z. et al. + 0 + ± <ul><li>Heparin </li></ul>Pepys J et al, Hedardt et al, Cockcroft et al. ? ++ ++ ++ <ul><li>Cromolyn </li></ul>Diamant et al., Leigh et al., Davis et al. ++ ++ ++ ++ <ul><li>LTRA </li></ul>Rafferty et al, Twentyman et al, Bentley et al. ? ? ± + <ul><li>H1 blockers </li></ul>Boulet LP et al., Fahy JV et al. +++ +++ +++ +++ <ul><li>Anti-IgE </li></ul>Gauvreau G.M. et al. ++ + + 0 <ul><li>Anti-CD11a </li></ul>Leckie M.J. et al. +++ 0 0 0 <ul><li>Anti-IL-5 </li></ul>Cockcroft DW et al. ? ++ +++ N/A Single dose after EAR Van Der Star et al., Swystun VA. et al. +++ +++ +++ ++ Regular Twentyman OP et al., Wong BJ. et al. 0 0 mask +++ <ul><li>LA β A </li></ul>Yu DYC et al., Cockcroft DW et al. 0 0 + + <ul><li>Anticholinergic </li></ul>Hendeles L et al., Cockcroft DW et al. ? 0 + + <ul><li>Theophylline </li></ul>Cockcroft DW et al. ++ ++ +++ 0 <ul><li>ICS : Single dose </li></ul>Bryan S.A. et al. +++ ± 0 0 <ul><li>IL-12 </li></ul>+ 0 LAR ++ +++ EAR 0 0 AHR ? 0 EOS Bianco S. et al. <ul><li>Furosemide </li></ul>Hedardt B et al., Cockcroft DW et al. <ul><li>β 2 agonists (conventional) </li></ul>References Drug
  • 28. Summary of BPT <ul><li>D irect BPT (e.g. M ethacholine) : h ighly S ensitive & function best to exclude A sthma when N eg T est & current question able s ymptoms </li></ul><ul><li>I nterpretation of M ethacholine BPT : N ormal expiratory flow rates (e.g. FEV1) & C linical currency of suspicious symptoms (at least previous few days) </li></ul><ul><li>I ndirect BPT : more S pecific (less sensitive) for A sthma & function best to C onfirm Dx, C hallenges of choice ?EIB </li></ul><ul><li>Allergen (selective) BPT : limited to research  P athogenesis of asthma , E valuation Rx for asthma </li></ul>
  • 30. Nasal Provocation Test <ul><li>Indications & Contraindications </li></ul><ul><li>Outcomes of nasal provocation </li></ul><ul><li>Methods of Nasal provocation </li></ul><ul><li>Nasal allergen provocation </li></ul><ul><li>NPT with physical, chemical & biochemical stimuli </li></ul>
  • 31. Clinical Indications for NPT <ul><li>1. A ssess role of A llergens implicated by p t Hx when Neg skin testing & R AST </li></ul><ul><li>2. C onfirm clinical relevance of specific allergen causing AR when multiple skin test positive </li></ul><ul><li>3. C onfirm S pecific O ccupational R hinitis includ e F ood-induced nasal symptoms </li></ul><ul><li>4. I dentify N on - standardized or N ovel A llergen in nasal target, possibly by undertaking NPT using preparation of A llergen </li></ul><ul><li>5. D etermine if nasal application of allergen induce extranasal symptoms (e.g. conjunctiva, middle ear, sinus, lower airways) </li></ul><ul><li>6. C onfirm A llergen in A sthmatic pts for whom BPT may not safe </li></ul><ul><li>7. D etermine N asal hyperreactivity using bradykinin </li></ul><ul><li>8. D etermine N asal reactivity before starting IT causing AR </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6 th ed. 2003; 644-55.
  • 32. Scientific Indications for NPT <ul><li>1. I nvestigate P hysiologic, M orphologic & C ellular of A llergen-induced immediate & late-phase responses & dose-dependent nature </li></ul><ul><li>2. A ssess N asal airways response to A llergens & other provocative agents and changes in bronchial responsiveness </li></ul><ul><li>3. E xamine drugs Rx effects on E arly, L ate-phase, N onspecific & other aspects of airway dis. </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6 th ed. 2003; 644-55.
  • 33. Contraindications for NPT <ul><li>Absolute </li></ul><ul><li>1. Acute bact. or viral Rhinitis or Sinusitis </li></ul><ul><li>2. Exacerbation of A llergic dis . </li></ul><ul><li>3. Previous anaphylactic reaction to A llergen </li></ul><ul><li>4. Pregnancy </li></ul><ul><li>5 . Coexisting severe general dis . es p. C ardiopulm dis . </li></ul><ul><li>Relative </li></ul><ul><li>1. Episode of R hinitis in last 2 - 4 wks . </li></ul><ul><li>2. Nasal Sx in last 6 to 8 wks . </li></ul><ul><li>3. Nasal pathology eg. Polyps, Atrophic rhinitis, Deviated nasal septum </li></ul><ul><li>4 . Treatment with certain medications </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6 th ed. 2003; 644-55.
  • 34. Washout periods for different drugs before NPT Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94. 3 days Chromones, nasal None Inhaled bronchodilators 7 days Leukotriene (cysLT1) receptor antagonists 1 day α -adrenergic agonists, oral or nasal 3 days Antihistamines, nasal 3–10 days Antihistamines, oral None Inhaled corticosteroids 7 days Corticosteroids, oral 7 days Corticosteroids, nasal Withdrawal Medications
  • 35. Local delivery systems <ul><li>Syringe </li></ul><ul><li>Dropper </li></ul><ul><li>Pipette, Micropipette </li></ul><ul><li>Nasal Metered-dose Pump Spray </li></ul><ul><li>Filter paper disc </li></ul><ul><li>Nasal pool device </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 36. Filter paper disc Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 37. Exposure Chambers <ul><li>Allergens : Pollen, Cat, Dust mite </li></ul><ul><li>Pollutants : ETS, CO 2 </li></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 38. Outcomes of NPT <ul><li>Subjectives : Symptoms </li></ul><ul><li>Objectives </li></ul><ul><ul><li>Measurements of Nasal patency </li></ul></ul><ul><ul><ul><li>Nasal Peak Flow </li></ul></ul></ul><ul><ul><ul><li>Rhinomanometry </li></ul></ul></ul><ul><ul><ul><li>Acoustic Rhinometry </li></ul></ul></ul><ul><ul><li>Nasal Secretion : Mediators, Cytokines </li></ul></ul><ul><ul><li>Nasal Cells & Tissue </li></ul></ul><ul><ul><li>M ucociliary transport </li></ul></ul><ul><ul><li>E ustachian tube function </li></ul></ul>
  • 39. Symptom outcome <ul><li>S neezing, P ruritus, R hinorrhea, P osterior nasal drainage, N asal congestion </li></ul><ul><li>A ddition O cular symptoms : L acrimatio n, Conjuctivitis </li></ul><ul><li>V alidity : S ubjectiv e except N umber of S neezes </li></ul><ul><li>M ost common scale ranges from 0 to 3 : 0 ‘no symptom’, 1 ‘mild’, 2 ‘moderate’, 3 ‘severe’ </li></ul><ul><li>Others : Thirteen-Point Symptom Score Method , Likert scales , VAS ( parametric statistical analyses ) </li></ul><ul><li>End points (T otal symptom score ) : not standardized , vary considerably, questionable reproducibility (no large-scale studies ) </li></ul>Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55. Middleton’s Allergy : principles and practice. 7th ed. 2008; 1281-94.
  • 40. Nasal Peak Flow <ul><li>Peak Flow Meter </li></ul><ul><li>Nasal Peak Expiratory Flow (NPEF) </li></ul><ul><li>Nasal Peak Inspiratory Flow (NPIF) </li></ul>
  • 41. Rhinomanometry <ul><li>Active vs. Passive </li></ul><ul><li>Anterior vs. Posterior </li></ul><ul><li>Pressure-Flow curve  Nasal Airway Resistance(NAR) at 75,150, 300 Pascals (ICSR) </li></ul>
  • 42. Acoustic Rhinometry <ul><li>S ound impulse is directed into single nasal passag e & E choes reflected from nasal walls </li></ul><ul><li>M inimum cross-sectional area at specific distance from entrance of the nares  “N asal cavity v olume ” </li></ul>
  • 43. Nasal Cells & Tissue <ul><li>Blown secretions </li></ul><ul><li>Nasal lavage </li></ul><ul><li>Mucosal imprint </li></ul><ul><li>Nasal swab </li></ul><ul><li>Nasal scraping </li></ul><ul><li>Nasal brushing </li></ul><ul><li>Nasal biopsy </li></ul>
  • 44. Nasal Cytology & Tissue Adapted from Ann Allergy Asthma Immunol 2001; 86:355-365. & Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94. - - + Inadq. Specimen, poor reproducibility E as y , Non-invasive <ul><li>Blown secretion </li></ul>+ + + - + - Lymp + + + - + - Mono + Pain, Trauma, Bleeding All mucosal layers <ul><li>Biopsy </li></ul>+ No deep mucosal layers E as y , R epea tibility , well tolerated both E pi . & S ecretions <ul><li>Scraping </li></ul>+ Pain, Trauma, Bleeding No deep mucosal layers E as y , time-course studies <ul><li>Brushing </li></ul>+ D iluted to variable extent E as y , R epea tibility , both E pi . & S ecretions <ul><li>Lavage </li></ul>+ Operator’ technique mucus may interfere identification of cells both E pi . & S ecretions <ul><li>Mucosal imprint </li></ul>+ poor reproducibility E as y , Non-invasive <ul><li>Swab </li></ul>Disadvantages Eo Advantages Methods
  • 45. Response of Unilateral NPT <ul><li>- MC degranulation : Histamine, Tryptase, LTs & others </li></ul><ul><li>- Histamine ≈ H1 receptor  vascular permeability & secretion </li></ul><ul><li>- Histamine ≈ Norciceptive n. receptor  Itching, sensation of congestion </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Norciceptive n.  Neuropeptides : - SP  Glandular secretion - CGRP  Vasodilation - ‘Axon Responses’ NASONASAL REFLEX
  • 46. Nasal Allergen Provocation Test <ul><li>Guidelines : No International available, some European countries </li></ul><ul><li>Assess relations btw AR & associated illnesses (Asthma, Conjunctivitis, Rhinosinusitis & Otitis media) </li></ul><ul><li>Repeated Allergen Provocations : </li></ul><ul><ul><li>O nce daily for 1 wk. </li></ul></ul><ul><ul><li>Demonstrated persistent symptoms develop after several days of allergen dosing & Inflammatory changes approx. in natural dis. </li></ul></ul><ul><ul><li>Used to assess efficacy of Rx </li></ul></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 47. Ann Allergy Asthma Immunol 2001; 86:355-365.
  • 48. Allergen challenge-induced leukocyte influx in nasal lavage fluids Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 49. Causes of FP & FN NPT results <ul><li>False-Positive Results </li></ul><ul><li>Use of preservatives (e.g., phenol, glycerol, benzalkonium chloride) </li></ul><ul><li>Changes in temperature </li></ul><ul><li>Changes in osmolarity </li></ul><ul><li>Recent airway illness (e.g., rhinitis) </li></ul><ul><li>Allergen extract concentration greater than 1:500 w/v </li></ul><ul><li>False-Negative Results </li></ul><ul><li>Use of medicines contraindicated for NPT </li></ul><ul><li>Atrophic rhinitis </li></ul><ul><li>Nasal polyps </li></ul><ul><li>Recent nasal surgery </li></ul><ul><li>Chronic sinus disease </li></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55..
  • 50. NPT with Physical, Chemical & Biochemical stimuli <ul><li>Physical stimuli </li></ul><ul><li>Neural & Irritant stimuli </li></ul><ul><li>Biochemical stimuli </li></ul>
  • 51. NPT with Physical stimuli <ul><li>Cold air : sensorineural activation & mast cell mediator release, ability to keep nasal mucosa hydrated (hyperosmolarity of nasal secretions & epi. shedding), tend to be general state of nasal hyperresponsivenes </li></ul><ul><li>Hyperosmolar solutions : </li></ul><ul><ul><li>Hyperosmolar Sodium chloride </li></ul></ul><ul><ul><li>Mannitol </li></ul></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 52. NPT with Neural & Irritant stimuli <ul><li>Capsaicin : Vanilloid receptor TRPV1 (on Unmyelinated, slow-conduct sensory nerve fibers) </li></ul><ul><ul><li>Burning sensation & Rhinorrhea </li></ul></ul><ul><ul><li>Unilat. NPT  Bilat. secretory response indicating generation of central, nasonasal reflex </li></ul></ul><ul><ul><li>High dose : Plasma extravasation & Inflammatory infiltrate ( presume capsaicin cause Inflam Neuropeptides release from nerve endings ) </li></ul></ul><ul><ul><li>↑ Nasal Capsaicin responsiveness in AR, but not Non-allergic Rhinitis </li></ul></ul><ul><li>Irritants & Air pollutants : </li></ul><ul><ul><li>Indoor : ETS, Cleaning products (eg. Chlorine or Ammonia) </li></ul></ul><ul><ul><li>Outdoor : Ozone, DEP, Volatile organic compounds </li></ul></ul>Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 53. NPT with Biochemical stimuli <ul><li>Histamine </li></ul><ul><li>Methacholine </li></ul><ul><li>Other mediators of allergic reactions </li></ul><ul><li>Neuropeptides </li></ul><ul><li>Adenosine 5’-monophosphate (AMP) </li></ul>
  • 54. Unilateral NPT with H istamine & M ethacholine Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94. <ul><li>Histamine induces contralateral secretory response while M ethacholine does not </li></ul><ul><li>H istamine generates central r eflex efferent arm of which stimulates submucosal glands in nostril opposite to challenge ( N asonasal reflex ) </li></ul>
  • 55. NPT with Neuropeptides <ul><li>Neuropeptides released from : </li></ul><ul><li>Sensory nerve endings (unmyelinated, slow-conducting C-fibers) containing various neuropeptides granules, mostly Tachykinins (Substance P & Neurokinin A) released upon neural activation, exert local inflam activity </li></ul><ul><li>Nasal cholinergic (e.g., vasoactive intestinal peptide) </li></ul><ul><li>Sympathetic nerves (e.g., neuropeptide Y) </li></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 56. NPT with Adenosine 5’-monophosphate (AMP) <ul><li>MC degranulation & sensory n. stimuli </li></ul><ul><li>AMP induce </li></ul><ul><ul><li>↑ Nasal symptoms &  Nasal Airflow only in AR </li></ul></ul><ul><ul><li>↑ Nasal lavage histamine & tryptase </li></ul></ul><ul><li>Medications inh. nasal response to AMP NPT : Antihistamines, LT modifiers, Nasal steroids & Heparin </li></ul>Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
  • 57. Summary of NPT <ul><li>NPT : Study Pathophysiology of Rhinitis, Pharmacodynamic & Medications against Rhinitic disorders, DDx of Rhinitis </li></ul><ul><li>Outcomes : Nasal symptoms, Changes in nasal patency, amount & content of Nasal secretions and Mucosal tissue </li></ul><ul><li>Allergen NPT : most studies, Acute (Early) & Late response, MC mediator release & intense symptoms  more indolent symptoms & inflam cell infiltrate </li></ul><ul><li>Physical, Irritant, Pollutants & Biochemical stimuli NPT : Assess various function of nasal mucosa eg. sensory nerves, submucosal glands & nasal vasculature </li></ul>
  • 58. QUIZ
  • 59. <ul><li>W hich of the following stimuli for bronchial provocation challenge testing is independent of mast cell activation? </li></ul><ul><li>a. Methacholine </li></ul><ul><li>b. Cold air </li></ul><ul><li>c. Exercise </li></ul><ul><li>d . Adenosine 5’-monophosphate </li></ul>
  • 60. <ul><li>W hich of the following bronchoprovocation tests is the best predictor for developing asthma? </li></ul><ul><li>a. Exercise </li></ul><ul><li>b. Mannitol </li></ul><ul><li>c. Methacholine </li></ul><ul><li>d . Eucapneic voluntary hyperpnea </li></ul>
  • 61. <ul><li>W hich of the following medications inhibits both the early & late phase reaction to inhalation allergen challenge? </li></ul><ul><li>a. Albuterol </li></ul><ul><li>b. Fexofenadine </li></ul><ul><li>c. Single dose of prednisolone </li></ul><ul><li>d . Nedocromil sodium </li></ul>
  • 62. <ul><li>NPT is contraindicat ed when the patient ? </li></ul><ul><li>a. has received oral steroid within 40 days </li></ul><ul><li>b. is p regnancy </li></ul><ul><li>c. receive an antihistamine 2 wks. ago </li></ul><ul><li>d. is asthmatic </li></ul>
  • 63. <ul><li>In w hich of the following conditions does nasal cytology have the greatest diagnostic utility? </li></ul><ul><li>a. A llergic rhinitis </li></ul><ul><li>b. Acute bacterial sinusitis </li></ul><ul><li>c. Acute viral sinusitis </li></ul><ul><li>d . Non-allergic rhinitis with eosinophilia </li></ul>
  • 64. <ul><li>Indications for the use of NPT in clinical practice include all of the following EXCEPT: </li></ul><ul><li>a. To confirm the role of allergen in cases of disagreement of patient’s history and skin testing and/or RAST </li></ul><ul><li>b. For the diagnosis of occupational allergic rhinitis </li></ul><ul><li>c. To identify a novel allergen causing allergic rhinitis </li></ul><ul><li>d. To confirm nasal reactivity to allergen before starting IT </li></ul><ul><li>e. To prove the allergic nature of asthma when corresponding bronchial allergen provocation tests are postivie </li></ul>
  • 65. <ul><li>Which of the following is NOT an absolute contraindication for NPT? </li></ul><ul><li>a. Acute period of allergic rhinitis </li></ul><ul><li>b. Mild asthma in remission </li></ul><ul><li>c. Previous anaphylactic reaction to an allergen </li></ul><ul><li>d. Acute viral or bacterial rhinitis and sinusitis </li></ul><ul><li>e. Pregnancy </li></ul>
  • 66. <ul><li>Which of these statements is false? </li></ul><ul><li>a. NPT can be done 4 wks after episode of allergic or infectious rhinitis </li></ul><ul><li>b. Polyps, atrophic rhinitis & deviated nasal septum are absolute contraindications for NPT </li></ul><ul><li>c. NPT can be done 6 wks after nasal or sinus surgery </li></ul><ul><li>d. Nasal congestion can result from oral contraceptives and preparations containing sulfite preservatives </li></ul><ul><li>e. NPT should not be done in patients with restricted lung capacity (TLC ,60%) </li></ul>
  • 67. <ul><li>A positive NPT is determined by: </li></ul><ul><li>a. The maximum allergen dose that patient received </li></ul><ul><li>b. Self-report scoring of clinical symptoms </li></ul><ul><li>c. 10-cm linear visual analog scales of symptoms </li></ul><ul><li>d. Measures of nasal patency </li></ul><ul><li>e. The assessment of clinical symptoms scores, nasal secretion, and nasal patency measurements </li></ul>
  • 68. <ul><li>Which of these statements is false? </li></ul><ul><li>a. NPT is a well standardized method and is frequently used in clinical practice in the United States </li></ul><ul><li>b. NPT has shown promise for the diagnosis of allergic and occupational rhinits </li></ul><ul><li>c. The analysis of mechanisms of NPT responses may lead to a more appropriate and focused therapy </li></ul><ul><li>d. There is a wide variety of NPT test techniques for research </li></ul><ul><li>e. NPT provides useful information about the pathogenesis of airway diseases </li></ul>
  • 69. Thank you

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