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

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Page 1: Nasal and Bronchial Provocation Tests

Nasal & Nasal & Bronchial Bronchial

Provocation Provocation TestTestP. Putivoranat, MD.P. Putivoranat, MD.

22/05/0922/05/09

Page 2: Nasal and Bronchial Provocation Tests

Bronchial Bronchial Provocation TestProvocation Test Airway hyperresponsiveness & Airway hyperresponsiveness & Measurement Measurement

Non-selective BPTNon-selective BPT Direct airway hyperresponsiveness Direct airway hyperresponsiveness Indirect airway Indirect airway

hyperresponsiveness hyperresponsiveness Clinical utility Clinical utility

Selective BPTSelective BPT Allergen BPTAllergen BPT Occupational BPTOccupational BPT

SummarySummary

Page 3: Nasal and Bronchial Provocation Tests

Bronchoprovocation Bronchoprovocation stimulistimuliNon-selectiveNon-selective SelectiveSelective

DirectDirect ImmunologicImmunologic HistamineHistamine MetacholineMetacholine ProstaglandinsProstaglandins LeukotrienesLeukotrienes

AllergenAllergen

High MW prot-containingHigh MW prot-containing

IgE mediatedIgE mediated OccupationalOccupational

Low MW sensitizerLow MW sensitizer

Mechanism uncertainMechanism uncertain

IndirectIndirect Non-ImmunologicNon-Immunologic

Physical : Physical : ExerciseExercise EVHEVH Cold airCold air Non-isotonic aerosolsNon-isotonic aerosols

Pharmacological : Pharmacological : AMPAMP PropanololPropanolol BradykininBradykinin MannitolMannitol

ASAASA NSAIDsNSAIDs Food additives (?)Food additives (?)

Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy :principles and practice. 7th ed. 2008; 1295-308.

Page 4: Nasal and Bronchial Provocation Tests

Non-Selective Non-Selective Bronchial Bronchial

Provocation TestProvocation Test

Page 5: Nasal and Bronchial Provocation Tests

Metacholine Metacholine vsvs Histamine challengesHistamine challenges

Methacholine Methacholine :: synthetic derivative of Acetylch oline

metabolized more slowly by cholinesterase metabolized more slowly by cholinesterase blocked or lessened by atropine or similar anticholiner blocked or lessened by atropine or similar anticholiner

gic agents gic agents more commonly used more commonly used & & preferredpreferred

HH istamine istamine :: more systemic side effects more systemic side effects ((headacheadac he,flushing he,flushing & & hoarsenesshoarseness)) , less reproducible BHR , less reproducible BHR

Similar mechanism :Similar mechanism : Direct activating Direct activating contraction of Bronchial smooth m. after binding contraction of Bronchial smooth m. after binding to Cholinergic receptors (& H receptor)to Cholinergic receptors (& H receptor)

Am J Respir Crit Care Med 2000; 161: 309-29.Clin Exp Allergy 2004; 34: 9-16.

Page 6: Nasal and Bronchial Provocation Tests

Contraindications for Contraindications forMetacholine challenge testMetacholine challenge test Absolute : Absolute :

Severe airflow limita Severe airflow limita tion( FEV1 tion( FEV1 < < 50%pr ed 50%pr ed

i ct ed or i ct ed or < < 10. L) 10. L) Hear t at t ack or Hear t at t ack or SS trokei trokei

n last 3 mo n last 3 mo UUUUUUUUUUUU UUUUUUUUUUUUU UUUUUUUUUUUUUUUU UUUUUUUUUUUUU UUUU

ol i c BP ol i c BP > > 200, or di 200, or di astolic BP astolic BP > > 100100

UUUUU UUUUU AAUUUUU UUUUUUUUUU UUUUUysmysm

Relative : Relative : Moderate airflow limit Moderate airflow limit

ation ( FEV1 ation ( FEV1 < < 60%pr e 60%pr e di ct ed or di ct ed or < < 15. 15.

L)L) UUUUUUUUU UU UUUUUUUUUUUUUUU UU UUUUUU

-maccept abl e qual i t -maccept abl e qual i t y spi r omet r y y spi r omet r y

Pr egnancyPr egnancy UUUUUUU UUUUUUUUUUUUUU UUUUUUU UUUUUUU UUU UUUUUUU UUU CC holinesteraseinhmedi c holinesteraseinhmedi c

ation (for myasthenia ation (for myastheniagravis)gravis)

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

Page 7: Nasal and Bronchial Provocation Tests

FFactors Decrease actors Decrease Bronchial ResponsivenessBronchial Responsiveness

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

Page 8: Nasal and Bronchial Provocation Tests

FFactors Increase actors Increase Bronchial ResponsivenessBronchial Responsiveness

*Studies of acute effects of smoking on airway hyperreactivity & UUUUUUUUUUUU UUUUUUUUU U estingar e not consi st ent .

UUUUU UU UUUU UUUUUUUU UU U UUUUU UUUUU UUUUUU UUUU UUU UU UUUUUUU UU UUUUUUUUU UUUUUUUU UU UUUUUUU UUUU UU UUUUU UUU U UUU UUUUU UUUUUU UUUUUUUUUU UUUUUUUU UU UUUUUUU UUUU UU UUUUU UUU U UUU UUUUU UUUUUU UUUUUUU

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

FactorFactor Duration of Effect Duration of Effect

Exposure to environmental Ags 1 3– wk

Occupational sensitizers Months

Respiratory infection 3 6– wk

Air pollutants 1 wk

Cigarette smoke Uncertain*

Chemical irritants Days to months

Page 9: Nasal and Bronchial Provocation Tests

Hypothetical methacholine dos Hypothetical methacholine dos e–response curves e–response curves

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 10: Nasal and Bronchial Provocation Tests

2 Metacholine 2 Metacholine challenge methodschallenge methods

Am J Respir Crit Care Med 2000; 161: 309-29.Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

False False NegativeNegative

Page 11: Nasal and Bronchial Provocation Tests

Metacholine challenge testMetacholine challenge test

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

Page 12: Nasal and Bronchial Provocation Tests

CC ut points ut points of of Methacholine BPTMethacholine BPT

mainly from the tidal breathing method

1. 1. NormalNormal – PC – PC2020

>16 mg/m >16 mg/ml.l.

2. 2. BorderlineBorderline – PC – PC2020

4 4 -- UUUU16 UUUU16 l.l.

3. 3. Mild AHR Mild AHR – PC – PC2020

1 1 -- 4mg/m 4mg/ml.l.

4. 4. Moderate AHR Moderate AHR – PC – PC2020

025. 025. -- 1mg/m 1mg/ml.l.

5. 5. Marked AHR Marked AHR – PC – PC2020

< 0.25 / < 0.25 /ml.ml. AHR severity AHR severity ≠ ≠ Asthma severityAsthma severity

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

Page 13: Nasal and Bronchial Provocation Tests

PPediatricediatric BPTBPT AA ge ge ≥≥ 6 yrs 6 yrs. ( . ( UUUUUUUUUUUUUU spirometryspirometry ) ) Too young : auscultation, transcut. Too young : auscultation, transcut.

PPtctcOO22, plethysmograph, plethysmograph Cut point : same as adultCut point : same as adult Metacholine challenge test Metacholine challenge test

Prefer the Tidal breathing methodPrefer the Tidal breathing method Best sensitivity & specificity : PCBest sensitivity & specificity : PC2020 3-4 3-4

mg/ml.mg/ml.Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 14: Nasal and Bronchial Provocation Tests

Indirect Airway Indirect Airway HyperresponsivenesHyperresponsivenes

ss ExerciseExercise Hyperventilation Hyperventilation : EVH, : EVH,

Standardized Cold airStandardized Cold air Non-Isotonic aerosols Non-Isotonic aerosols : Hypertonic : Hypertonic

saline, Distilled watersaline, Distilled water AMP (Adenosine Monophosphate)AMP (Adenosine Monophosphate) Dry Powder MannitolDry Powder Mannitol Other Indirect ChallengeOther Indirect Challenge : :

Propanolol, Bradykinins, Tachykinins, Propanolol, Bradykinins, Tachykinins, SOSO22

Clin Exp Allergy 2004; 34: 9-16.Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 15: Nasal and Bronchial Provocation Tests

Mechanism of Indirect Mechanism of Indirect BronchialBronchial ChallengeChallenge

Eur Respir J 2003; 21: 1050-68Eur Respir J 2003; 21: 1050-68

Page 16: Nasal and Bronchial Provocation Tests

Methacholine Methacholine vs.vs. Non-selective Non-selective Indirect BPTIndirect BPTMethodsMethods MechanismMechanism TargetTarget MeasureMeasure IntervalInterval DurationDuration NoteNote

MethacholineMethacholine DirectDirect Methacholine Methacholine 0.03-16 mg/ml0.03-16 mg/ml

PCPC202030 & 90 30 & 90

sec.sec. 5 min.5 min. 50 min.50 min. High AHR SensitivityHigh AHR Sensitivity Less Asthma SpecificLess Asthma Specific

ExerciseExercise OsmoticOsmotic

Exercise 80-90%

Max.HR for 6 min.

FEV1 10-15%

min. 5 min. 30 min. Excessive dry airway

Eucapnic Eucapnic Voluntary Voluntary HyperpneaHyperpnea

OsmoticOsmoticDry air with 5% CO2 for 6 min.

10%

FEV1

10-15 min.

10-15 min.

Excessive dry airway Similar to Exercise

Cold airCold air OsmoticOsmotic18 ºC 0% Humidity

PD2010-15 min.

3 min. 12 min. Excessive dry airway

Non-isotonic Non-isotonic aerosolsaerosols

OsmoticOsmotic4.5% NSS Ultrasonic nebulizer

PC2030 & 90

sec.0.5-8 min.

Induce Sputum Australia

MannitolMannitol OsmoticOsmoticDry powder

Mannitol 0-635 mg.

PD15 1 min. 2 min.20-25 min.

Normal: PD15 > 635 mg Less dose limitation Sensitivity

AMPAMP Non -Non -OsmoticOsmotic

Adenosine Monophosphat

e up to 400 mg.

PC2030 & 90

sec.5 min. 40 min.

Europe

Adapted from Eur Respir J 2003; 21: 1050-68 & Middleton’s Allergy :principles and practice. 7th ed. 2008; 1295-308.

Page 17: Nasal and Bronchial Provocation Tests

Clinical Utility of Clinical Utility of Non-Selective BPTNon-Selective BPT DiagnosisDiagnosis Occupational AsthmaOccupational Asthma Drug effects & Drug effects &

Treatment monitoringTreatment monitoring PrognosisPrognosis

Page 18: Nasal and Bronchial Provocation Tests

Non-Selective BPTNon-Selective BPT for for DiagnosisDiagnosis

Diagnostic test of AsthmaDiagnostic test of Asthma

Direct BPTDirect BPT : : N N ormal spirometry prior to ormal spirometry prior to MMee thacholine challenge relates safety thacholine challenge relates safety & &

correct correct interpretainterpretation tion NN - on asthmatic airflow obstruction (e- on asthmatic airflow obstruction (eg.g. CO CO

PD) PD) ↑↑AHR AHR to direct stimuli to direct stimuli & & highly correlat highly correlat ed with degree of ed with degree of 1FEV 1FEV & & most likely rel most likely rel

ated to obstruction ated to obstruction PPVPPV of histamine PC20 of histamine PC20 < < 8 mg/mL in rando 8 mg/mL in rando

m population was shown to have m population was shown to have PPV <PPV < 5 5 0% 0% PPV PPV for for AA sthma sthma DxDx will improve wit will improve wit

h h ↑↑ pretest probability pretest probabilityAm J Respir Crit Care Med 2000; 161: 309-29.

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 19: Nasal and Bronchial Provocation Tests

Non-Selective BPTNon-Selective BPT for for DiagnosisDiagnosis

Diagnostic test of Asthma, EIBDiagnostic test of Asthma, EIB

Indirect BPTIndirect BPT : : highly specific highly specific but but not not very sensitive very sensitive

CC onfirm onfirm Dx Dx of of AA sthma sthma SS ubjects might have EIB ubjects might have EIB : : challenges challenges

should be choice for should be choice for II nternational ath nternational ath letic agencies, letic agencies, AA rmed forces, rmed forces, PP olice f olice f

orces, SCUBA diving orces, SCUBA divingAm J Respir Crit Care Med 2000; 161: 309-29.

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 20: Nasal and Bronchial Provocation Tests

FN & FP results for Non-FN & FP results for Non-selective BPTselective BPT

False NegativeFalse Negative False PositiveFalse Positive

DirectDirect

(Metacholine)(Metacholine)

Elite or high-intensity athletesElite or high-intensity athletes MedicationsMedications

Functional antagonist ( Functional antagonist ( ββ2 2 agonist)agonist)

Specific antagonist (anti-Specific antagonist (anti-muscarinic)muscarinic) Symptoms or exposures not Symptoms or exposures not clinically currentclinically current TLC inhalations during TLC inhalations during challengechallenge (Eosinophilic bronchitis)(Eosinophilic bronchitis)

Normals (5-15%)Normals (5-15%) Rhinitis (20-40%)Rhinitis (20-40%) Sedentary individuals with Sedentary individuals with subclinical asthmasubclinical asthma

IndirectIndirect

(Exercise, (Exercise, EVH, etc.)EVH, etc.)

Common in mild or well-Common in mild or well-controlled asthmacontrolled asthma Medication effects as aboveMedication effects as above

Should be infrequentShould be infrequent

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 21: Nasal and Bronchial Provocation Tests

Selective Selective Bronchial Bronchial

Provocation TestProvocation Test

Page 22: Nasal and Bronchial Provocation Tests

Allergen BPTAllergen BPT Allergen-induced Early Asthmatic Allergen-induced Early Asthmatic

ResponseResponse Allergen-induced Late Asthmatic Allergen-induced Late Asthmatic

Response Response Allergen-induced increase in AHRAllergen-induced increase in AHR Allergen-induced EosinophilsAllergen-induced Eosinophils Standardized Allergen Challenge methodStandardized Allergen Challenge method Other Allergen Challenge methodsOther Allergen Challenge methods Medications Inhibit Allergen-induced Medications Inhibit Allergen-induced

responsesresponses

Page 23: Nasal and Bronchial Provocation Tests

Allergen-induced EARAllergen-induced EAR

32% early Assss ssss ssssssss

• MMaxax..1010-- 20mins or slightly longer 20mins or slightly longer& R& R esolves spont esolves spont.. 2 2-- 3 hrs. 3 hrs.• TimeTime-- course similar to bronchoconstriction course similar to bronchoconstriction

following exercise, but may be slightly more following exercise, but may be slightly moreprolonged.prolonged.

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 24: Nasal and Bronchial Provocation Tests

Allergen-induced LARAllergen-induced LAR

Late ≥ 4 0 %Essss 33%

Dual Asthmatic response

• 4-54-5 hrs. hrs. after Challengeafter Challenge, , may persist may persist ≥≥ 12 hrs.12 hrs.• IgE mediatedIgE mediated & Airway Inflammation& Airway InflammationMiddleton’s Allergy : principles and practice. 7th ed. 2008;

1295-308.

Page 25: Nasal and Bronchial Provocation Tests

Allergen-induced increase in Allergen-induced increase in AHRAHR

AHR: 2-3 hrs. after Challenge, may persist several days

DAR

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 26: Nasal and Bronchial Provocation Tests

Allergen-induced Allergen-induced EosinophilsEosinophils

SS putum exam putum exam & S& S -aline-aline induced sputum induced sputum

↑↑ Eosinophils Eosinophils in in DAR but DAR but not isolated EAR not isolated EAR & & not i not i

n n II nterval phase (2–3 hr nterval phase (2–3 hr s) in dual respon s) in dual responsese

↑↑AA irway respons irway responsee in in LALA R R & & ↑↑EE osinophils togeth osinophils togeth er and er and IInhnh.. by by CCorticostorticost

eroidseroids Study of AStudy of Asthmasthma pathopatho

genesis genesis & I& I nvestigation nvestigation of new of new medicationsmedications

Allergy 2 0 0 6 : 611118.

PlaceboPlacebo Grass pollensGrass pollens

Middleton’s Allergy : principles and practice. 7th ed. 2008; 1295-308.

Page 27: Nasal and Bronchial Provocation Tests

Medications inhibit Medications inhibit Allergen-induced responses Allergen-induced responses DrugDrug EAREAR LARLAR AHRAHR EOSEOS ReferencesReferences

β2 agonists (conventional) +++ 0 0 0 Hedardt B et al., Cockcroft DW et al.

LAβA +++ mask 0 0 Twentyman OP et al., Wong BJ. et al.

Anticholinergic + + 0 0 Yu DYC et al., Cockcroft DW et al.

Theophylline + + 0 ? Hendeles L et al., Cockcroft DW et al.

ICS : Single dose 0 +++ ++ ++ Cockcroft DW et al.

Single dose after EAR N/A +++ ++ ? Cockcroft DW et al.

Regular ++ +++ +++ +++ Van Der Star et al., Swystun VA. et al.

Cromolyn ++ ++ ++ ? Pepys J et al, Hedardt et al, Cockcroft et al.

LTRA ++ ++ ++ ++ Diamant et al., Leigh et al., Davis et al.

H1 blockers + ± ? ? Rafferty et al, Twentyman et al, Bentley et al.

Anti-IgE +++ +++ +++ +++ Boulet LP et al., Fahy JV et al.

Anti-CD11a 0 + + ++ Gauvreau G.M. et al.

Anti-IL-5 0 0 0 +++ Leckie M.J. et al.

IL-12 0 0 ± +++ Bryan S.A. et al.

Heparin ± + 0 + Diamant Z. et al.

Furosemide ++ + 0 ? Bianco S. et al.

Page 28: Nasal and Bronchial Provocation Tests

SummarySummary of BPTof BPT DD i r ect i r ect BPTBPT (e.g. (e.g. MM ethacholine) ethacholine) : h: h ighly ighly SS ensitive ensitive & & function function

best t o excl ude best t o excl ude AA sthma when sthma when NN eg eg TT est est & & curcur r ent quest i on r ent quest i onable sable s ymptoms ymptoms

II nterpretation of nterpretation of MM et hachol i ne et hachol i ne BPTBPT : N: N ormal ormal expiratory flow rates (e.g. FEV1 ) expiratory flow rates (e.g. FEV1 ) & C& C linical c linical c

urrency of suspicious symptoms (at least prev urrency of suspicious symptoms (at least prev ious few days) ious few days)

II ndi r ect ndi r ect BPT : BPT : mor e mor e SS pecific (less sensitive) f pecific (less sensitive) f or or AA sthma sthma & & function best to function best to CC onfi r m onfi r mDx, CDx, Chh

allenges of choice allenges of choice ?EIB ?EIB Allergen(selective) Allergen(selective) BPT :BPT : limited to research limited to research PP athogenesis of athogenesis of

asthmaasthma, E, E valuation valuation RxRx for asthma for asthma

Page 29: Nasal and Bronchial Provocation Tests
Page 30: Nasal and Bronchial Provocation Tests

Nasal Provocation Nasal Provocation TestTest

Indications & Indications & ContraindicationsContraindications

Outcomes of nasal Outcomes of nasal provocation provocation

Methods of Nasal provocationMethods of Nasal provocation Nasal allergen provocation Nasal allergen provocation NPT with physical, chemical & NPT with physical, chemical &

biochemical stimuli biochemical stimuli

Page 31: Nasal and Bronchial Provocation Tests

Clinical Indications for Clinical Indications forNPTNPT 1. 1. AA ssess role of ssess role of AA llergens implicated by llergens implicated by pp t t HxHx when when

Neg Neg skin testing skin testing & R& RASTAST 2. 2. CC onfirm clinical relevance of specific allergen causing onfirm clinical relevance of specific allergen causingARAR when when multiple skin test positive multiple skin test positive 3. 3. CC onfirm onfirm SS pecific pecific OO ccupational ccupational RRhinitishinitis includ includee FF -ood i-ood i

nduced nasal symptoms nduced nasal symptoms 4. 4. II dentify dentify NNonon--standardizedstandardized or or NN ovel ovel AAllergenllergen in nas in nas

al target, possibly by undertaking NPT using preparatio al target, possibly by undertaking NPT using preparatio n of n of AAllergenllergen

5. 5. DD etermine if nasal application of allergen induce etermine if nasal application of allergen induceextranasal extranasal symptomssymptoms (e.g. conjunctiva, middle ear, (e.g. conjunctiva, middle ear,

sinus, lower airways) sinus, lower airways) 6. 6. CC onfirm onfirm AA llergen in llergen in AA sthmatic pts for whom sthmatic pts for whom BPTBPT may may

not safe not safe 7. 7. DD etermine etermine NN asal hyperreactivity using asal hyperreactivity using bradykininbradykinin 8. 8. DD etermine etermine NN asal reactivity before starting asal reactivity before starting IT IT causi causi

ng ng ARAR Ann Allergy Asthma Immunol 2001; 86:355-365.

Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55.

Page 32: Nasal and Bronchial Provocation Tests

Scientific Indications fo Scientific Indications fo r NPT r NPT

1. 1. II nvestigate nvestigate PP hysiologic, hysiologic, MMorpholoorpholo gic gic & C& C ellular of ellular of AA - llergen induced i- llergen induced i

mmediate mmediate & & - late phase responses- late phase responses && - dose dependent nature - dose dependent nature 2. 2. AA ssess ssess NN asal airways response to asal airways response to AA

llergens llergens & & other provocative agents other provocative agents and changes in bronchial responsiv and changes in bronchial responsiv

enesseness 3. 3. EE xamine drugs xamine drugs RxRx effects on effects on EE arly, arly,LL - ate phase,- ate phase, NN onspecific onspecific & & other asp other asp

ects of airway dis. ects of airway dis.Ann Allergy Asthma Immunol 2001; 86:355-365.

Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55.

Page 33: Nasal and Bronchial Provocation Tests

Contraindications for N Contraindications for NPTPTAbsoluteAbsolute

1. 1. Acute bact. or viral Acute bact. or viral Rhinitis or SinusitisRhinitis or Sinusitis

2. Exacerbation of 2. Exacerbation of AAUUUUUUUUUU UUUUUUU UUU..

3. 3. Previous Previous UUUUUUUUUUUUUUUUUUUUUU UUUUUUUU UU UUUUUUUU to Ato Allerller

gen gen

4. Pregnancy 4. Pregnancy

55 UUUUUUUUUU UUUUUU U. UUUUUUUUUU UUUUUU U. eneral dis eneral dis.. UU UUp.p. CCUUUUUUUU opulm dis opulm dis..

RelativeRelative

1. Episode of 1. Episode of RRUUUUUUU UUUUUUUU U UUUU U2 UUUU U2 -- U UU4 U UU4 ..

2. Nasal 2. Nasal SxSx 6 8inlast t o 6 8inlast t owkswks..

3 . 3 . Nasal pathology Nasal pathology eg. Polyps, Atrophic eg. Polyps, Atrophic rhinitis, Deviated rhinitis, Deviated nasal septumnasal septum

44 . Tr eat ment wi t h cer . Tr eat ment wi t h cer tain medications tain medications

Ann Allergy Asthma Immunol 2001; 86:355-365.

Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55.

Page 34: Nasal and Bronchial Provocation Tests

Washout periods for different dr Washout periods for different dr ugs before NPT ugs before NPT

MedicationsMedications WithdrawWithdrawalal

sssss, sssss, 7 days 7 days

Corticosteroids, oral Corticosteroids, oral 7 days 7 days

Antihistamines, nasal Antihistamines, nasal 3 days 3 days

Antihistamines, oral Antihistamines, oral s310 s310

ssssss s( 1 ) s( 1 )

eceptor antagonists eceptor antagonists 7 days 7 days

αα- adrenergic agonists, o- adrenergic agonists, o ral or nasal ral or nasal 1 day 1 day

Chromones, nasal Chromones, nasal 3 days 3 days

sssssss ssssssssssssssssssssss sssssssssssssss s ssss sss Inhaled corticosteroids Inhaled corticosteroids s ssss sss

Ann Allergy Asthma Immunol 2001; 86:355-365.

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

Page 35: Nasal and Bronchial Provocation Tests

Local delivery systemsLocal delivery systems SyringeSyringe DropperDropper Pipette, Pipette,

MicropipetteMicropipette Nasal Metered-Nasal Metered-

dose Pump Spraydose Pump Spray Filter paper discFilter paper disc Nasal pool deviceNasal pool device

Ann Allergy Asthma Immunol 2001; 86:355-365.

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

Page 36: Nasal and Bronchial Provocation Tests

Filter paper discFilter paper disc

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

Page 37: Nasal and Bronchial Provocation Tests

Exposure ChambersExposure Chambers

Allergens : Allergens : Pollen, Cat, Dust Pollen, Cat, Dust mitemite

Pollutants : Pollutants : ETS, COETS, CO22Middleton’s Allergy : principles and practice. 7th ed. 2008; 1281-94.

Page 38: Nasal and Bronchial Provocation Tests

Outcomes of NPTOutcomes of NPT Subjectives : SymptomsSubjectives : Symptoms Objectives Objectives

Measurements of Nasal patencyMeasurements of Nasal patency Nasal Peak FlowNasal Peak Flow RhinomanometryRhinomanometry Acoustic RhinometryAcoustic Rhinometry

Nasal Secretion : Mediators, Nasal Secretion : Mediators, CytokinesCytokines

Nasal Cells & TissueNasal Cells & Tissue MM ucociliary transport ucociliary transport EE ustachian tube function ustachian tube function

Page 39: Nasal and Bronchial Provocation Tests

Symptom outcome Symptom outcome SS neezing, neezing, PP ruritus, ruritus, RR hinorrhea, hinorrhea, PP osterior nasal dr osterior nasal dr

ainage,ainage, N N asal congestion asal congestion AA ddition ddition OO cular symptoms cular symptoms : L: Lacrimatioacrimation, n,

ConjuctivitisConjuctivitis VV alidity alidity : S: Subjectivubjective except Ne except N umber of umber of SS neezes neezes MM ost common scale ranges from 0 to 3 ost common scale ranges from 0 to 3 : : 0 ‘no sy 0 ‘no sy

mptom’, 1 ‘mild’, 2 ‘moderate’, 3 ‘severe’ mptom’, 1 ‘mild’, 2 ‘moderate’, 3 ‘severe’ Others : Others : - Thi r t een Poi nt Sympt omScor e Met hod- Thi r t een Poi nt Sympt omScor e Met hod, ,

Li ker t scal es Li ker t scal es , VAS (, VAS ( parametric statistical analy parametric statistical analy ses ses ))

End poi nt s End poi nt s (T(T otal symptom score otal symptom score)) : : not standard not standardizedized,, vary considerably, vary considerably, questionable questionable reproducibireproducibi

l i t y l i t y (no(no - large scale studies - 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.

Page 40: Nasal and Bronchial Provocation Tests

Nasal Peak FlowNasal Peak Flow Peak Flow Peak Flow

MeterMeter Nasal Peak Nasal Peak

Expiratory Expiratory Flow (NPEF) Flow (NPEF)

Nasal Peak Nasal Peak Inspiratory Inspiratory Flow (NPIF)Flow (NPIF)

Page 41: Nasal and Bronchial Provocation Tests

RhinomanometryRhinomanometry ActiveActive vs. vs. PassivePassive AnteriorAnterior vs. vs. PosteriorPosterior Pressure-Flow curvePressure-Flow curve Nasal Airway Nasal Airway

Resistance(NAR) at 75,150, 300 Pascals Resistance(NAR) at 75,150, 300 Pascals (ICSR) (ICSR)

Page 42: Nasal and Bronchial Provocation Tests

Acoustic RhinometryAcoustic Rhinometry SS ound impulse ound impulse is directed into single nasal

passage & E choes reflected from nasal walls

M - inimum cross sectional area at specific di stance from entrance of the nares “N“N asal asal

cavitycavity v volumeolume””

Page 43: Nasal and Bronchial Provocation Tests

Nasal Cells & Tissue Nasal Cells & Tissue Blown secretionsBlown secretions Nasal lavageNasal lavage Mucosal imprintMucosal imprint Nasal swabNasal swab Nasal scrapingNasal scraping Nasal brushingNasal brushing Nasal biopsyNasal biopsy

Page 44: Nasal and Bronchial Provocation Tests

Nasal Cytology & TissueNasal Cytology & TissueMethodsMethods AdvantagesAdvantages DisadvantagesDisadvantages EoEo LympLymp MonoMono

Blown secretionBlown secretion Easy, Non-invasiveInadq. Specimen,

poor reproducibility + - -

LavageLavageEasy, Repeatibility,

both Epi. & SecretionsDiluted to variable extent + - -

Mucosal imprintMucosal imprint both Epi. & Secretions

Operator’ technique

mucus may interfere

identification of cells

+ + +

SwabSwab Easy, Non-invasive poor reproducibility + - -

ScrapingScrapingEasy, Repeatibility,

well tolerated

both Epi. & Secretions

No deep mucosal layers + + +

BrushingBrushing Easy, time-course studiesPain, Trauma, Bleeding

No deep mucosal layers+ + +

BiopsyBiopsy All mucosal layers Pain, Trauma, Bleeding + + +

Adapted from Ann Allergy Asthma Immunol 2001; 86:355-365. & Middleton’s Allergy : principles and practice. 7th ed. 2008; 1281-94.

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Response of Unilateral Response of Unilateral NPTNPT

Ann Allergy Asthma Immunol 2001; 86:355-365.

- MC degranulation : Histamine, Tryptase, LTs & others

- Histamine ≈ H1 receptor vascular permeability & secretion

- Histamine ≈ Norciceptive n. receptor Itching, sensation of congestion

Norciceptive n. Neuropeptides :

- SP Glandular secretion- CGRP Vasodilation- ‘Axon Responses’

NASONASAL REFLEXNASONASAL REFLEX

Page 46: Nasal and Bronchial Provocation Tests

Nasal Allergen Nasal Allergen Provocation TestProvocation Test

Guidelines :Guidelines : No International No International available, some European countriesavailable, some European countries

Assess relations btw AR & associated Assess relations btw AR & associated illnesses (Asthma, Conjunctivitis, illnesses (Asthma, Conjunctivitis, Rhinosinusitis & Otitis media)Rhinosinusitis & Otitis media)

Repeated Allergen Provocations : Repeated Allergen Provocations : OOnce daily for 1 wk. nce daily for 1 wk. Demonstrated persistent symptoms develop Demonstrated persistent symptoms develop

after several days of allergen dosing & after several days of allergen dosing & Inflammatory changes approx. in natural dis. Inflammatory changes approx. in natural dis.

Used to assess efficacy of RxUsed to assess efficacy of RxAnn Allergy Asthma Immunol 2001;

86:355-365. Middleton’s Allergy : principles and

practice. 7th ed. 2008; 1281-94.

Page 47: Nasal and Bronchial Provocation Tests

Ann Allergy Asthma Immunol 2001; 86:355-365.

Page 48: Nasal and Bronchial Provocation Tests

- Allergen challenge induced leukocyte i - Allergen challenge induced leukocyte i nflux in nasal lavage fluids nflux in nasal lavage fluids

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

Page 49: Nasal and Bronchial Provocation Tests

Causes of FP & FN NPT Causes of FP & FN NPT resultsresults

False-Positive ResultsFalse-Positive Results Use of preservatives Use of preservatives

(e.g., phenol, glycerol, (e.g., phenol, glycerol, benzalkonium chloride)benzalkonium chloride)

Changes in temperatureChanges in temperature Changes in osmolarityChanges in osmolarity Recent airway illness Recent airway illness

(e.g., rhinitis)(e.g., rhinitis) Allergen extract Allergen extract

concentration greater concentration greater than 1:500 w/vthan 1:500 w/v

False-Negative False-Negative ResultsResults

Use of medicines Use of medicines contraindicated for contraindicated for NPTNPT

Atrophic rhinitisAtrophic rhinitis Nasal polypsNasal polyps Recent nasal surgeryRecent nasal surgery Chronic sinus diseaseChronic sinus disease

Ann Allergy Asthma Immunol 2001; 86:355-365.

Middleton’s Allergy : principles and practice. 6th ed. 2003; 644-55..

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NPTNPT with Physical, Chemical with Physical, Chemical & Biochemical stimuli& Biochemical stimuli

Physical Physical stimulistimuli

Neural & Neural & Irritant stimuliIrritant stimuli

Biochemical Biochemical stimulistimuli

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NPTNPT with Physical stimuliwith Physical stimuli Cold airCold air : : sensorineural activation sensorineural activation

& mast cell mediator release, ability to & mast cell mediator release, ability to keep nasal mucosa hydrated keep nasal mucosa hydrated (hyperosmolarity of nasal secretions & (hyperosmolarity of nasal secretions & epi. shedding), tend to be general epi. shedding), tend to be general state of nasal hyperresponsivenesstate of nasal hyperresponsivenes

Hyperosmolar solutionsHyperosmolar solutions : : Hyperosmolar Sodium Hyperosmolar Sodium chloridechloride

MannitolMannitol Ann Allergy Asthma Immunol 2001; 86:355-365.

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

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NPTNPT with Neural & Irritant with Neural & Irritant stimulistimuli CapsaicinCapsaicin : : Vanilloid receptor TRPV1 (on Vanilloid receptor TRPV1 (on

Unmyelinated, slow-conduct sensory nerve fibers) Unmyelinated, slow-conduct sensory nerve fibers) Burning sensation & RhinorrheaBurning sensation & Rhinorrhea Unilat. NPT Unilat. NPT Bilat. secretory response indicating Bilat. secretory response indicating

generation of central, nasonasal reflexgeneration of central, nasonasal reflex High dose : Plasma extravasation & Inflammatory High dose : Plasma extravasation & Inflammatory

infiltrate ( presume capsaicin cause Inflam infiltrate ( presume capsaicin cause Inflam Neuropeptides release from nerve endings )Neuropeptides release from nerve endings )

↑ ↑ Nasal Capsaicin responsiveness in AR, but not Non-Nasal Capsaicin responsiveness in AR, but not Non-allergic Rhinitisallergic Rhinitis

Irritants & Air pollutantsIrritants & Air pollutants : : Indoor : ETS, Cleaning products (eg. Chlorine or Indoor : ETS, Cleaning products (eg. Chlorine or

Ammonia)Ammonia) Outdoor : Ozone, DEP, Volatile organic Outdoor : Ozone, DEP, Volatile organic

compoundscompoundsAnn Allergy Asthma Immunol 2001;

86:355-365. Middleton’s Allergy : principles and

practice. 7th ed. 2008; 1281-94.

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NPTNPT with Biochemical stimuliwith Biochemical stimuli HistamineHistamine MethacholineMethacholine Other mediators of Other mediators of

allergic reactions allergic reactions NeuropeptidesNeuropeptides Adenosine 5’-Adenosine 5’-

monophosphate (AMP)monophosphate (AMP)

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Unilateral Unilateral NPTNPT with with HH istamine istamine & M& Mee thacholine thacholine

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

• Histamine induces contralateral secretory response Histamine induces contralateral secretory response while while MM ethacholine does not ethacholine does not

• HH istamine generates central istamine generates central rr eflex efferent arm of w eflex efferent arm of w hich stimulates submucosal glands in nostril opposite t hich stimulates submucosal glands in nostril opposite t

o challenge ( o challenge ( NN asonasal reflex ) asonasal reflex )

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NPTNPT with Neuropeptideswith NeuropeptidesNeuropeptides released from : Neuropeptides released from : Sensory nerve endings (unmyelinated, Sensory nerve endings (unmyelinated,

slow-conducting C-fibers) containing slow-conducting C-fibers) containing various neuropeptides granules, mostly various neuropeptides granules, mostly Tachykinins (Substance P & Neurokinin Tachykinins (Substance P & Neurokinin A) released upon neural activation, exert A) released upon neural activation, exert local inflam activitylocal inflam activity

Nasal cholinergic (e.g., vasoactive Nasal cholinergic (e.g., vasoactive intestinal peptide) intestinal peptide)

Sympathetic nerves (e.g., neuropeptide Sympathetic nerves (e.g., neuropeptide Y)Y)

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

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NPTNPT with Adenosine 5’-with Adenosine 5’-monophosphate (AMP)monophosphate (AMP)

MC degranulation & sensory n. MC degranulation & sensory n. stimulistimuli

AMP induce AMP induce ↑ ↑ Nasal symptomsNasal symptoms & & Nasal Airflow Nasal Airflow

only in ARonly in AR ↑↑ Nasal lavage histamine & tryptaseNasal lavage histamine & tryptase

Medications inh. nasal response to Medications inh. nasal response to AMP NPT : Antihistamines, LT AMP NPT : Antihistamines, LT modifiers, Nasal steroids & Heparinmodifiers, Nasal steroids & Heparin

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

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SummarySummary of NPTof NPT NPT : Study Pathophysiology of Rhinitis, NPT : Study Pathophysiology of Rhinitis,

Pharmacodynamic & Medications against Rhinitic Pharmacodynamic & Medications against Rhinitic disorders, DDx of Rhinitisdisorders, DDx of Rhinitis

Outcomes : Nasal symptoms, Changes in nasal Outcomes : Nasal symptoms, Changes in nasal patency, amount & content of Nasal secretions patency, amount & content of Nasal secretions and Mucosal tissueand Mucosal tissue

Allergen NPT : most studies, Acute (Early) & Late Allergen NPT : most studies, Acute (Early) & Late response, MC mediator release & intense response, MC mediator release & intense symptoms symptoms more indolent symptoms & inflam more indolent symptoms & inflam cell infiltratecell infiltrate

Physical, Irritant, Pollutants & Biochemical stimuli Physical, Irritant, Pollutants & Biochemical stimuli NPT : Assess various function of nasal mucosa eg. NPT : Assess various function of nasal mucosa eg. sensory nerves, submucosal glands & nasal sensory nerves, submucosal glands & nasal vasculaturevasculature

Page 58: Nasal and Bronchial Provocation Tests

QUIZQUIZ

Page 59: Nasal and Bronchial Provocation Tests

WW hich of the following hich of the following stimuli for stimuli for bronchial provocation challenge bronchial provocation challenge testing is independent of mast testing is independent of mast cell activation?cell activation?

a. a. MethacholineMethacholine

b. b. Cold air Cold air

c. c. ExerciseExercise

dd . . Adenosine 5’-monophosphateAdenosine 5’-monophosphate

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WW hich of the following hich of the followingbronchoprovocation tests is the bronchoprovocation tests is the best predictor for developing best predictor for developing asthma?asthma?

a. Exercisea. Exercise b. b. Mannitol Mannitol

c. c. MethacholineMethacholine

dd . . Eucapneic voluntary hyperpneaEucapneic voluntary hyperpnea

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W hich of the following hich of the followingmedications inhibits both the medications inhibits both the early & late phase reaction to early & late phase reaction to inhalation allergen challenge?inhalation allergen challenge?

a. Albuterola. Albuterol b. b. FexofenadineFexofenadine c. c. Single dose of prednisoloneSingle dose of prednisolone

dd . . Nedocromil sodiumNedocromil sodium

Page 62: Nasal and Bronchial Provocation Tests

NPT NPT is is contraindicatcontraindicated when the ed when the patientpatient??

a. has received oral steroid a. has received oral steroid within 40 dayswithin 40 days b. b. is pis pregnancyregnancy

c. c. receive an antihistamine 2 receive an antihistamine 2 wks. agowks. ago

d. d. is asthmaticis asthmatic

Page 63: Nasal and Bronchial Provocation Tests

In wIn w hich of the following hich of the following conditions conditions does nasal cytology have the does nasal cytology have the greatest diagnostic utility?greatest diagnostic utility?

a. A a. Allergic rhinitisllergic rhinitis

b. b. Acute bacterial sinusitis Acute bacterial sinusitis

c. Acute viral sinusitis c. Acute viral sinusitis

dd . . Non-allergic rhinitisNon-allergic rhinitis with with eosinophiliaeosinophilia

Page 64: Nasal and Bronchial Provocation Tests

Indicationsf or t he use of NPT i n cl i ni cal pr act i ce i ncl ude Indicationsf or t he use of NPT i n cl i ni cal pr act i ce i ncl ude all of the following EXCEPT: all of the following EXCEPT:

a. To confirm the role of allergen in cases of disagree a. To confirm the role of allergen in cases of disagree ment of patient’s history and skin testing and/or RA ment of patient’s history and skin testing and/or RA

STST

b. For the diagnosis of occupational allergic rhinitis b. For the diagnosis of occupational allergic rhinitis

c. To identify a novel allergen causing allergic rhinitis c. To identify a novel allergen causing allergic rhinitis

d. To confirm nasal reactivity to allergen before starti d. To confirm nasal reactivity to allergen before starti ng ng ITIT

e. To prove the allergic nature of asthma when corre e. To prove the allergic nature of asthma when corre sponding bronchial allergen provocation tests are p sponding bronchial allergen provocation tests are p

ostivieostivie

Page 65: Nasal and Bronchial Provocation Tests

Which of the following is NOT an absolu Which of the following is NOT an absolu te contraindication for NPT? te contraindication for NPT?

a. Acute period of allergic rhinitis a. Acute period of allergic rhinitis

b. Mild asthma in remission b. Mild asthma in remission

c. Previous anaphylactic reaction to an c. Previous anaphylactic reaction to anallergenallergen

d. Acute viral or bacterial rhinitis and si d. Acute viral or bacterial rhinitis and sinusitisnusitis

e. Pregnancy e. Pregnancy

Page 66: Nasal and Bronchial Provocation Tests

Which of these statements is false? Which of these statements is false?

a. NPT can be done 4 wks after episode of allergic or i a. NPT can be done 4 wks after episode of allergic or i nfectious rhinitis nfectious rhinitis

b. Polyps, atrophic rhinitis b. Polyps, atrophic rhinitis & & deviated nasal septum a deviated nasal septum a re absolute contraindications for NPT re absolute contraindications for NPT

c. NPT can be done 6 wks after nasal or sinus surgery c. NPT can be done 6 wks after nasal or sinus surgery

d. Nasal congestion can result from oral contraceptiv d. Nasal congestion can result from oral contraceptiv es and preparations containing sulfite preservatives es and preparations containing sulfite preservatives

e. NPT should not be done in patients with restricted l e. NPT should not be done in patients with restricted l ung capacity (TLC ,60%) ung capacity (TLC ,60%)

Page 67: Nasal and Bronchial Provocation Tests

A positive NPT is determined by: A positive NPT is determined by:

a. The maximum allergen dose that patient rec a. The maximum allergen dose that patient receivedeived

- b. Self report scoring of clinical symptoms - b. Self report scoring of clinical symptoms

- c. 10 cm linear visual analog scales of sympto - c. 10 cm linear visual analog scales of symptomsms

d. Measures of nasal patency d. Measures of nasal patency

e. The assessment of clinical symptoms scores e. The assessment of clinical symptoms scores , nasal secretion, and nasal patency measure , nasal secretion, and nasal patency measure

mentsments

Page 68: Nasal and Bronchial Provocation Tests

Which of these statements is false? Which of these statements is false?

a. NPT is a well standardized method and is frequen a. NPT is a well standardized method and is frequen tly used in clinical practice in the United States tly used in clinical practice in the United States

b. NPT has shown promise for the diagnosis of aller b. NPT has shown promise for the diagnosis of aller gic and occupational rhinits gic and occupational rhinits

c. The analysis of mechanisms of NPT responses ma c. The analysis of mechanisms of NPT responses ma y lead to a more appropriate and focused therapy y lead to a more appropriate and focused therapy

d. There is a wide variety of NPT test techniques for d. There is a wide variety of NPT test techniques forresearchresearch

e. NPT provides useful information about the patho e. NPT provides useful information about the patho genesis of airway diseases genesis of airway diseases

Page 69: Nasal and Bronchial Provocation Tests

Thank youThank you