Nasal and Bronchial Provocation Tests

Nasal & Bronchial Provocation Test P. Putivoranat, MD. 22/05/09

Bronchial Provocation Test
Airway hyperresponsiveness & Measurement
Non-selective BPT
Direct airway hyperresponsiveness
Indirect airway hyperresponsiveness
Clinical utility
Selective BPT
Allergen BPT
Occupational BPT
Summary

Bronchoprovocation stimuli Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.
ASA
NSAIDs
Food additives (?)
Physical :
Exercise
EVH
Cold air
Non-isotonic aerosols
Pharmacological :
AMP
Propanolol
Bradykinin
Mannitol
Non-Immunologic Indirect
Allergen
High MW prot-containing
IgE mediated
Occupational
Low MW sensitizer
Mechanism uncertain
Histamine
Metacholine
Prostaglandins
Leukotrienes
Immunologic Direct Selective Non-selective

Non-Selective Bronchial Provocation Test

Metacholine vs Histamine challenges
Methacholine : synthetic derivative of A cetylcholine
metabolized more slowly by cholinesterase
blocked or lessened by atropine or similar anticholinergic agents
more commonly used & preferred
H istamine : more systemic side effects ( headache,flushing & hoarseness ) , less reproducible BHR
Similar mechanism : Direct activating contraction of Bronchial smooth m. after binding to Cholinergic receptors (& H receptor)
Am J Respir Crit Care Med 2000; 161: 309-29. Clin Exp Allergy 2004; 34: 9-16.

Contraindications for Metacholine challenge test
Absolute :
Severe airflow limitation (FEV1 < 50% predicted or < 1.0 L)
Heart attack or S troke in last 3 mo
Uncontrolled hypertension, systolic BP > 200, or diastolic BP > 100
Known A ortic aneurysm
Relative :
Moderate airflow limitation (FEV1 < 60% predicted or < 1.5 L)
Inability to perform acceptable-quality spirometry
Pregnancy
Nursing mothers
Current use C holinesterase inh medication (for myasthenia gravis)
Am J Respir Crit Care Med 2000; 161: 309-29.

F actors Decrease Bronchial Responsiveness Am J Respir Crit Care Med 2000; 161: 309-29.

F actors Increase Bronchial Responsiveness
*Studies of acute effects of smoking on airway hyperreactivity & methacholine challenge testing are not consistent.
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
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

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 practice. 7 th ed. 2008; 1295-308. False Negative

Metacholine challenge test Am J Respir Crit Care Med 2000; 161: 309-29.

C ut points of Methacholine BPT
mainly from the tidal breathing method
1. Normal – PC 20 >16 mg/m l.
2. Borderline – PC 20 4 - 16 mg/m l.
3. Mild AHR – PC 20 1 - 4 mg/m l.
4. Moderate AHR – PC 20 0.25 - 1 mg/m l.
5. Marked AHR – PC 20 < 0.25 mg/ ml.
AHR severity ≠ Asthma severity
Am J Respir Crit Care Med 2000; 161: 309-29.

P ediatric BPT
A ge ≥ 6 yrs . ( perform spirometry )
Too young : auscultation, transcut. P tc O 2 , plethysmograph
Cut point : same as adult
Metacholine challenge test
Prefer the Tidal breathing method
Best sensitivity & specificity : PC 20 3-4 mg/ml.
Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.

Indirect Airway Hyperresponsiveness
Exercise
Hyperventilation : EVH, Standardized Cold air
Non-Isotonic aerosols : Hypertonic saline, Distilled water
AMP (Adenosine Monophosphate)
Dry Powder Mannitol
Other Indirect Challenge : Propanolol, Bradykinins, Tachykinins, SO 2
Clin Exp Allergy 2004; 34: 9-16. Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

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 : principles and practice. 7 th ed. 2008; 1295-308.
Europe
40 min. 5 min. 30 & 90 sec. PC 20 Adenosine Monophosphate up to 400 mg. Non -Osmotic
AMP
High AHR Sensitivity
Less Asthma Specific
50 min. 5 min. 30 & 90 sec. PC 20 Methacholine 0.03-16 mg/ml Direct
Methacholine
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
Induce Sputum
Australia
PC 20 4.5% NSS Ultrasonic nebulizer Osmotic
Non-isotonic aerosols
Normal: PD 15 > 635 mg
Less dose limitation   Sensitivity
20-25 min. PD 15 Dry powder Mannitol 0-635 mg. Osmotic
Mannitol
Excessive dry airway
30 min.  FEV 1 10-15% Exercise 80-90% Max.HR for 6 min. Osmotic
Exercise
Similar to Exercise
 10% FEV 1 Dry air with 5% CO 2 for 6 min. Osmotic
Eucapnic Voluntary Hyperpnea
12 min. PD 20 18 º C 0% Humidity Osmotic
Cold air
Target Mechanism Duration Note Methods

Clinical Utility of Non-Selective BPT
Diagnosis
Occupational Asthma
Drug effects & Treatment monitoring
Prognosis

Non-Selective BPT for Diagnosis
Diagnostic test of Asthma
Direct BPT : N ormal spirometry prior to M ethacholine challenge relates safety & correct interpreta tion
N on-asthmatic airflow obstruction (e g. COPD) ↑ AHR to direct stimuli & highly correlated with degree of  FEV1 & most likely related to obstruction
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
Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.

Non-Selective BPT for Diagnosis
Diagnostic test of Asthma, EIB
Indirect BPT : highly specific but not very sensitive
C onfirm Dx of A sthma
S ubjects might have EIB : challenges should be choice for I nternational athletic agencies, A rmed forces, P olice forces, SCUBA diving
Am J Respir Crit Care Med 2000; 161: 309-29. Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.

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)
Should be infrequent
Common in mild or well-controlled asthma
Medication effects as above
Normals (5-15%)
Rhinitis (20-40%)
Sedentary individuals with subclinical asthma
Elite or high-intensity athletes
Medications
Functional antagonist ( β 2 agonist)
Specific antagonist (anti-muscarinic)
Symptoms or exposures not clinically current
TLC inhalations during challenge
(Eosinophilic bronchitis)
False Positive False Negative

Selective Bronchial Provocation Test

Allergen BPT
Allergen-induced Early Asthmatic Response
Allergen-induced Late Asthmatic Response
Allergen-induced increase in AHR
Allergen-induced Eosinophils
Standardized Allergen Challenge method
Other Allergen Challenge methods
Medications Inhibit Allergen-induced responses

Allergen-induced EAR 32% early A sthmatic response
M ax . 10 - 20 mins or slightly longer & R esolves spont . 2 - 3 hrs.
Time - course similar to bronchoconstriction following exercise, but may be slightly more prolonged.

Allergen-induced LAR Late ≥ 40% E arly 33% Dual Asthmatic response
4-5 hrs. after Challenge , may persist ≥ 12 hrs.
IgE mediated & Airway Inflammation

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.

Allergen-induced Eosinophils
S putum exam & S aline-induced sputum
↑ Eosinophils in DAR but not isolated EAR & not in I nterval phase (2–3 hrs) in dual respon se
↑ A irway respons e in LAR & ↑ E osinophils together and I nh . by C orticosteroids
Study of A sthma pathogenesis & I nvestigation of new medications
Allergy 2006: 61: 111–8 . Placebo Grass pollens Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1295-308.

Medications inhibit Allergen-induced responses Diamant Z. et al. + 0 + ±
Heparin
Pepys J et al, Hedardt et al, Cockcroft et al. ? ++ ++ ++
Cromolyn
Diamant et al., Leigh et al., Davis et al. ++ ++ ++ ++
LTRA
Rafferty et al, Twentyman et al, Bentley et al. ? ? ± +
H1 blockers
Boulet LP et al., Fahy JV et al. +++ +++ +++ +++
Anti-IgE
Gauvreau G.M. et al. ++ + + 0
Anti-CD11a
Leckie M.J. et al. +++ 0 0 0
Anti-IL-5
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 +++
LA β A
Yu DYC et al., Cockcroft DW et al. 0 0 + +
Anticholinergic
Hendeles L et al., Cockcroft DW et al. ? 0 + +
Theophylline
Cockcroft DW et al. ++ ++ +++ 0
ICS : Single dose
Bryan S.A. et al. +++ ± 0 0
IL-12
+ 0 LAR ++ +++ EAR 0 0 AHR ? 0 EOS Bianco S. et al.
Furosemide
Hedardt B et al., Cockcroft DW et al.
β 2 agonists (conventional)
References Drug

Summary of BPT
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
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)
I ndirect BPT : more S pecific (less sensitive) for A sthma & function best to C onfirm Dx, C hallenges of choice ?EIB
Allergen (selective) BPT : limited to research  P athogenesis of asthma , E valuation Rx for asthma

Nasal Provocation Test
Indications & Contraindications
Outcomes of nasal provocation
Methods of Nasal provocation
Nasal allergen provocation
NPT with physical, chemical & biochemical stimuli

Clinical Indications for NPT
1. A ssess role of A llergens implicated by p t Hx when Neg skin testing & R AST
2. C onfirm clinical relevance of specific allergen causing AR when multiple skin test positive
3. C onfirm S pecific O ccupational R hinitis includ e F ood-induced nasal symptoms
4. I dentify N on - standardized or N ovel A llergen in nasal target, possibly by undertaking NPT using preparation of A llergen
5. D etermine if nasal application of allergen induce extranasal symptoms (e.g. conjunctiva, middle ear, sinus, lower airways)
6. C onfirm A llergen in A sthmatic pts for whom BPT may not safe
7. D etermine N asal hyperreactivity using bradykinin
8. D etermine N asal reactivity before starting IT causing AR
Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6 th ed. 2003; 644-55.

Scientific Indications for NPT
1. I nvestigate P hysiologic, M orphologic & C ellular of A llergen-induced immediate & late-phase responses & dose-dependent nature
2. A ssess N asal airways response to A llergens & other provocative agents and changes in bronchial responsiveness
3. E xamine drugs Rx effects on E arly, L ate-phase, N onspecific & other aspects of airway dis.

Contraindications for NPT
Absolute
1. Acute bact. or viral Rhinitis or Sinusitis
2. Exacerbation of A llergic dis .
3. Previous anaphylactic reaction to A llergen
4. Pregnancy
5 . Coexisting severe general dis . es p. C ardiopulm dis .
Relative
1. Episode of R hinitis in last 2 - 4 wks .
2. Nasal Sx in last 6 to 8 wks .
3. Nasal pathology eg. Polyps, Atrophic rhinitis, Deviated nasal septum
4 . Treatment with certain medications

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

Local delivery systems
Syringe
Dropper
Pipette, Micropipette
Nasal Metered-dose Pump Spray
Filter paper disc
Nasal pool device

Filter paper disc Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.

Exposure Chambers
Allergens : Pollen, Cat, Dust mite
Pollutants : ETS, CO 2

Outcomes of NPT
Subjectives : Symptoms
Objectives
Measurements of Nasal patency
Nasal Peak Flow
Rhinomanometry
Acoustic Rhinometry
Nasal Secretion : Mediators, Cytokines
Nasal Cells & Tissue
M ucociliary transport
E ustachian tube function

Symptom outcome
S neezing, P ruritus, R hinorrhea, P osterior nasal drainage, N asal congestion
A ddition O cular symptoms : L acrimatio n, Conjuctivitis
V alidity : S ubjectiv e except N umber of S neezes
M ost common scale ranges from 0 to 3 : 0 ‘no symptom’, 1 ‘mild’, 2 ‘moderate’, 3 ‘severe’
Others : Thirteen-Point Symptom Score Method , Likert scales , VAS ( parametric statistical analyses )
End points (T otal symptom score ) : not standardized , vary considerably, questionable reproducibility (no large-scale studies )
Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55. Middleton’s Allergy : principles and practice. 7th ed. 2008; 1281-94.

Nasal Peak Flow
Peak Flow Meter
Nasal Peak Expiratory Flow (NPEF)
Nasal Peak Inspiratory Flow (NPIF)

Rhinomanometry
Active vs. Passive
Anterior vs. Posterior
Pressure-Flow curve  Nasal Airway Resistance(NAR) at 75,150, 300 Pascals (ICSR)

Acoustic Rhinometry
S ound impulse is directed into single nasal passag e & E choes reflected from nasal walls
M inimum cross-sectional area at specific distance from entrance of the nares  “N asal cavity v olume ”

Nasal Cells & Tissue
Blown secretions
Nasal lavage
Mucosal imprint
Nasal swab
Nasal scraping
Nasal brushing
Nasal biopsy

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
Blown secretion
+ + + - + - Lymp + + + - + - Mono + Pain, Trauma, Bleeding All mucosal layers
Biopsy
+ No deep mucosal layers E as y , R epea tibility , well tolerated both E pi . & S ecretions
Scraping
+ Pain, Trauma, Bleeding No deep mucosal layers E as y , time-course studies
Brushing
+ D iluted to variable extent E as y , R epea tibility , both E pi . & S ecretions
Lavage
+ Operator’ technique mucus may interfere identification of cells both E pi . & S ecretions
Mucosal imprint
+ poor reproducibility E as y , Non-invasive
Swab
Disadvantages Eo Advantages Methods

Response of Unilateral NPT
- MC degranulation : Histamine, Tryptase, LTs & others
- Histamine ≈ H1 receptor  vascular permeability & secretion
- Histamine ≈ Norciceptive n. receptor  Itching, sensation of congestion
Ann Allergy Asthma Immunol 2001; 86:355-365. Norciceptive n.  Neuropeptides : - SP  Glandular secretion - CGRP  Vasodilation - ‘Axon Responses’ NASONASAL REFLEX

Nasal Allergen Provocation Test
Guidelines : No International available, some European countries
Assess relations btw AR & associated illnesses (Asthma, Conjunctivitis, Rhinosinusitis & Otitis media)
Repeated Allergen Provocations :
O nce daily for 1 wk.
Demonstrated persistent symptoms develop after several days of allergen dosing & Inflammatory changes approx. in natural dis.
Used to assess efficacy of Rx

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 ed. 2008; 1281-94.

Causes of FP & FN NPT results
False-Positive Results
Use of preservatives (e.g., phenol, glycerol, benzalkonium chloride)
Changes in temperature
Changes in osmolarity
Recent airway illness (e.g., rhinitis)
Allergen extract concentration greater than 1:500 w/v
False-Negative Results
Use of medicines contraindicated for NPT
Atrophic rhinitis
Nasal polyps
Recent nasal surgery
Chronic sinus disease
Ann Allergy Asthma Immunol 2001; 86:355-365. Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55..

NPT with Physical, Chemical & Biochemical stimuli
Physical stimuli
Neural & Irritant stimuli
Biochemical stimuli

NPT with Physical stimuli
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
Hyperosmolar solutions :
Hyperosmolar Sodium chloride
Mannitol

NPT with Neural & Irritant stimuli
Capsaicin : Vanilloid receptor TRPV1 (on Unmyelinated, slow-conduct sensory nerve fibers)
Burning sensation & Rhinorrhea
Unilat. NPT  Bilat. secretory response indicating generation of central, nasonasal reflex
High dose : Plasma extravasation & Inflammatory infiltrate ( presume capsaicin cause Inflam Neuropeptides release from nerve endings )
↑ Nasal Capsaicin responsiveness in AR, but not Non-allergic Rhinitis
Irritants & Air pollutants :
Indoor : ETS, Cleaning products (eg. Chlorine or Ammonia)
Outdoor : Ozone, DEP, Volatile organic compounds

NPT with Biochemical stimuli
Histamine
Methacholine
Other mediators of allergic reactions
Neuropeptides
Adenosine 5’-monophosphate (AMP)

Unilateral NPT with H istamine & M ethacholine Middleton’s Allergy : principles and practice. 7 th ed. 2008; 1281-94.
Histamine induces contralateral secretory response while M ethacholine does not
H istamine generates central r eflex efferent arm of which stimulates submucosal glands in nostril opposite to challenge ( N asonasal reflex )

NPT with Neuropeptides
Neuropeptides released from :
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
Nasal cholinergic (e.g., vasoactive intestinal peptide)
Sympathetic nerves (e.g., neuropeptide Y)

NPT with Adenosine 5’-monophosphate (AMP)
MC degranulation & sensory n. stimuli
AMP induce
↑ Nasal symptoms &  Nasal Airflow only in AR
↑ Nasal lavage histamine & tryptase
Medications inh. nasal response to AMP NPT : Antihistamines, LT modifiers, Nasal steroids & Heparin

Summary of NPT
NPT : Study Pathophysiology of Rhinitis, Pharmacodynamic & Medications against Rhinitic disorders, DDx of Rhinitis
Outcomes : Nasal symptoms, Changes in nasal patency, amount & content of Nasal secretions and Mucosal tissue
Allergen NPT : most studies, Acute (Early) & Late response, MC mediator release & intense symptoms  more indolent symptoms & inflam cell infiltrate
Physical, Irritant, Pollutants & Biochemical stimuli NPT : Assess various function of nasal mucosa eg. sensory nerves, submucosal glands & nasal vasculature

W hich of the following stimuli for bronchial provocation challenge testing is independent of mast cell activation?
a. Methacholine
b. Cold air
c. Exercise
d . Adenosine 5’-monophosphate

W hich of the following bronchoprovocation tests is the best predictor for developing asthma?
a. Exercise
b. Mannitol
c. Methacholine
d . Eucapneic voluntary hyperpnea

W hich of the following medications inhibits both the early & late phase reaction to inhalation allergen challenge?
a. Albuterol
b. Fexofenadine
c. Single dose of prednisolone
d . Nedocromil sodium

NPT is contraindicat ed when the patient ?
a. has received oral steroid within 40 days
b. is p regnancy
c. receive an antihistamine 2 wks. ago
d. is asthmatic

In w hich of the following conditions does nasal cytology have the greatest diagnostic utility?
a. A llergic rhinitis
b. Acute bacterial sinusitis
c. Acute viral sinusitis
d . Non-allergic rhinitis with eosinophilia

Indications for the use of NPT in clinical practice include all of the following EXCEPT:
a. To confirm the role of allergen in cases of disagreement of patient’s history and skin testing and/or RAST
b. For the diagnosis of occupational allergic rhinitis
c. To identify a novel allergen causing allergic rhinitis
d. To confirm nasal reactivity to allergen before starting IT
e. To prove the allergic nature of asthma when corresponding bronchial allergen provocation tests are postivie

Which of the following is NOT an absolute contraindication for NPT?
a. Acute period of allergic rhinitis
b. Mild asthma in remission
c. Previous anaphylactic reaction to an allergen
d. Acute viral or bacterial rhinitis and sinusitis
e. Pregnancy

Which of these statements is false?
a. NPT can be done 4 wks after episode of allergic or infectious rhinitis
b. Polyps, atrophic rhinitis & deviated nasal septum are absolute contraindications for NPT
c. NPT can be done 6 wks after nasal or sinus surgery
d. Nasal congestion can result from oral contraceptives and preparations containing sulfite preservatives
e. NPT should not be done in patients with restricted lung capacity (TLC ,60%)

A positive NPT is determined by:
a. The maximum allergen dose that patient received
b. Self-report scoring of clinical symptoms
c. 10-cm linear visual analog scales of symptoms
d. Measures of nasal patency
e. The assessment of clinical symptoms scores, nasal secretion, and nasal patency measurements

Which of these statements is false?
a. NPT is a well standardized method and is frequently used in clinical practice in the United States
b. NPT has shown promise for the diagnosis of allergic and occupational rhinits
c. The analysis of mechanisms of NPT responses may lead to a more appropriate and focused therapy
d. There is a wide variety of NPT test techniques for research
e. NPT provides useful information about the pathogenesis of airway diseases

Thank you

Nasal and Bronchial Provocation Tests

by Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Chulalongkorn University on Jun 03, 2009

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Nasal and Bronchial Provocation Tests — Presentation Transcript