Since the 1970s the BronchoprovocationCommittee of the American Academy of Allergy and Immunologyhasbeenconcernedwith the standardization of inhalation provocation-challengeprocedures.The 1975publication by the Committee in THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY’ has remained a valuable resourcefor clinicians. The multicenter evaluation of methacholine (Provocholine; Roche Laboratories, Nutley, N.J.), which involved many of the Committeemembers,led to FDA approval of the product in December 1986. Until that time, only methacholineobtainedwithout FDA sanctionwas available for challenge. The current protocol for Provocholineinvolves the inhalation of saline followed by five concentrations of Provocholine: 0.025, 0.25, 2.5, 10, and 25 mg/ml. With the dosimetermethod, five inhalations of eachof theseconcentrationsis delivered, followed by spirometry. A decreasein FEV, of ~20% from the baselineFEV, after saline denotessignificant sensitivity, the degreeof which is conveyedby the PD,,. Although tidal volume method has not been used during studies to evaluateProvocholine, it has been usedas an alternativeto the dosimetermethod, since studies have demonstratedsimilar results for both methods.’The tidal volume methodinvolves the direct delivery of methacholinefrom a Wright nebulizer or an alternativetype that is known to have similar characteristics. The patient breathesfrom a face mask or mouthpiece, receiving saline diluent and then progressive concentrationsof methacholine, each for 2 minutes, with spirometry performed after this procedure. It is now commonly acceptedthat methacholine sensitivity is an indiginousfeatureof asthma,although it exists with other conditions als~.~ Methacholine challenge is a valuable clinical tool in supporting a clinical diagnosisof asthma.It is a valuable research tool in the study of pharmacologicmechanismsand the duration of action of drugs for asthma and for evaluating the natural history of bronchial hyperresponsiveness. From the BronchoprovocationCommittee, American Academy of Allergy and Immunology. Reprint requests:Gail Shapiro, MD, NW Asthma/Allergy Center, PS 4.540Sand Point Way NE, Seattle, WA 981053914. 111135452

Provocativedoseof methacholine causinga

To evaluatethe impact of the availability of methacholine challengeas a clinical tool, the Bronchoprovocation Committee designeda questionnairethat was mailed to the membership.Pour thousandquestionnaires were distributed and 1150 were returned. The Committeewas favorably impressedby the magnitude of the responseand by the interest in the challenge techniqueconveyedby the many commentsthat were received. It is likely that this responseram underreports the number of physicians who are interestedin and use bronchoprovocation,since we are awarethat in many group practices, only one questionnairewas returnedas representativeof the opinions of an entire group of physicians. The key issuesof the questionnaireare summarized in Table I, and the numberof responsesto eachquestion are indicated. Many of the respondersoffered comments. A group of individuaksechoedthe theme that they prefer to rely on a therapeutict&l to define airway responsiveness,although the reasonsvaried greatly (Table II). Among the comments assigning positive value to the clinical chalIengearetestimonials to the benefits for sorting diagnostic dilemmas and making decisionsabout long-term use of anti-inflammatory therapy (TableIII). Negativecommentsabout the procedurewere concernedwith overuse of procedures, the possibility of falsely equating positive reactivity with clinical asthma,andoccasionaladverse reactionsby patientsand staff (TableIV). Responders were askedfor their suggestions,and thesewere numerous. The suggestionsincluded requestsfor less expensive Provocholine, premixed concentrations, fewer concentrations, a simpler protocol, and metered-doseinhalers for delivery (Table V). These comments require some historical perspective on Provocholine. Before Hoffmann-LaRoche came forward to fund researchwith methacholine, aimed at achievingFDA approval, the drug was only



776 Bronchoprovocation committee report

TABLE I. Bronchoprovocation


(total number

1. Do you or have you used methacholinefor bronchoprovocationchallenge No Yes Provocholine Methacholine Not familiar with methacholine Do not seepatientswith lower respiratory tract symptoms Methacholinechallengenot useful No expertiseto perform challenge Concernedwith patient illness as a result of challenge Other 2. Using methacholineprior to availability of Provocholine Yes No 3. Where challengesare performed Office Hospital Other 4. Patient groups challengeis used Children 3-5 (yr) Children 6-12 (yr) Teenagers Adults 5. Who perform challenge Myself Technician Nurse Other 6. Physicianon premises Yes No 7. Averageusage Daily Weekly Monthly Other (see comments) 8. Administration Continuousnebulization with face mask Intermittent nebulizationwith dosimeter Other (see comments) 9. Dosesused Packageinsert protocol Other protocol 10. Difficulty with use Dilution preparation Yes No Moderateto severesymptoms Yes NO

of questionnaires



412 665 359 356 31 8 66 165 146 159 499 424 429 400 74 62 375 537 700 190 379 251 90 730 14 32 148 273 305 186 421 104 393 222 10 536 78 429


89 3





TABLE I. Cont’d

1I. Adversereactionsamongstaff Coughing Yes No Wheezing Yes No Other lower respiratorysymptoms Yes No Other symptoms Yes No 12. Challengecontributionto care Improveddiagnosisof asthma Yes No Knowledgeleadsto therapeuticdecisions Yes No

63 511

15 48X I.!

50s 650 41 242


TABLE IV. Comments on negative values of methacholine challenge

TABLE Il. Comments on use of mathacholine challenge

Prefer therapeutictrial Believe it shouldbe performedin a hospital setting Afraid of litigation Too busy Too expensivefor patients Have not neededit enoughto justify Have considered,but not madethe effort Local hospital or pulmonologistdoesit-more cheaplymadeby hospital or pharmacy Not enoughvolume to justify cost in office Not reimbursableby insurance

TABLE Ill. Comments on positive methachoiine challenge



value of

Avoids inappropriateuse of asthmamedications Helpful for workup of coughand cough-variant asthma Helpful for occupationalasthmaquestions Helps with decisionabout anti-inflammatorydrugs

Overusefor money Staff reactionif not ventedwell One late reaction Diagnosisof asthmawithout clinical correlates Given to known subjectswith asthma __I~ TABLE V. Suggestions

Make it less expensive Make it easierto make dilutions Premixedbottles Metered-doseinhalerswith variousdoses Better availability of dosimeter Simplify protocol Need clearerexplanationof equipmentand protwo

C o m m itteeresultedin a protocolthat was brieferthan previousprotocolswhile it remainedboth safe and discriminating.The five dosagelevels (0.025, 0.25, 2.5, 10, and 25 mg/ml) appearedto satisfy those goals. There has been some sentiment that a availableas a laboratoryreagent,not for humanuse. 5 mg/ml concentrationwould be a helpful addition when a patient’slevel of responsewas assessed. It is Although the likelihood of profitability was small, unfortunatethat thecurrentpackagingof Provocholine Hoffmann-L,aRoche fundedm u lticentertrials with a truncatedversion of the protocol publishedby the doesnot allow for this addition.Nevertheless,to our BronchoprovocationC o m m ittee in 1975. Several knowledge,therehavebeenno seriousadverseevents yearsandmuchdiscussionby theBronchoprovocation as a result of the jump from 2.5 to 10 m g i m l. Con-

778 Bronchoprovocation committee report

sideringthe cost/benefit ratio, it is unlikely that the pharmaceuticalindustry or the FDA will perceivea needto pursuechangesin the current protocol or in delivery methods. As a generalguidelinefor clinical practice,patients who have a 20% or more drop in PBV, at 0.025 mg/ml are consideredto have severebronchial hyperresponsiveness,whereas 0.25 and 2.5 mg/ml levels indicate moderateand 10 and 25 mg/ml concentrationsindicatem ild hyperresponsiveness. For the actualdeterminationof a PDzO,a dose-response curve graph must be constructed,plotting changein FBV, againstthe log of methacholineconcentration.In general, a PDu, ~0.2 mg/ml is consideredsevere;>0.2 to 2 mg/ml, moderate;and >2 to 25 mg/ml, m ild. Thereareonly m inimal dataconcerningdropsin peak expiratory flow rate and forced expiratory flow rate between25% and 75% that correlatewith this 20% changein FEV,. Although severelyand moderately hyperresponsivepatientsare likely to have a degree of asthmathat m ight best be managedby long-term therapy, m ild respondersare less likely to need aggressivetherapy.Thesevery generalcommentsshould serveonly as guidelines.The physicianwho ordersa provocativechallengemust interpretthe resultsin the context of the patient’s particularhistory. Numerous reviewson the clinical and researchuse of methacholine challengeareavailable.Althoughcertainpharmacologic interventionshave the ability to alter methacholine sensitivity, bronchial hyperresponsiveness will often remain the same,even when good control of asthmasymptomsandpulmonaryfunction stability


have occurred.Thus, serial measurements of methacholinesensitivity in clinical practice,as a methodto judge asthmacontrol, cannotbe recommended. Some respondersexpresseddesire to learn more about methacholinechallengeand, specifically, to have more input concerningthe equipmentinvolved and the procedure. At upcoming meetings of the American Academy of Allergy and Immunology, hands-onworkshopswill addresstheseneeds.These new workshopswill allow physiciansto “walk through the procedure.”Presentations anddemonstrations will also take place at Allied Health Programs.The BronchoprovocationCommitteeis gratifiedthat its interest in inhalation challengehas permeatedboth research and clinical arenas. Gail G. Shapiro, MD, Chairperson Ronald A. Sinon, MD, Past chairperson American Academy of Allergy and Immunology Bronchoprovocation Committee

REFERENCES 1. Chai H, Farr RS, FroehlichLA, et al. Standard&ion of bronchial inhalationchallengeprocedores.J AUER~YCLm Irmmo~ 1975;56:323. 2. Ryan G, Dolovich MB, RobertsRS, et al. Standardizationsof inhalation bronchoprovocationtests: hvo techniquesof aerosol generation and inhalation compared. Am Rev Respir Dis 1981;123:195-9. 3. Townley RG, Hopp RJ. Inhalation methods for the sntdy of airway responsiveness. J ALLERGY CLINImnmo~ 1987;80:11l27.


In the articleby M ichoudet al. entitled,“Effect of salbutamol on gastroesophageal reflux in healthyvolunteers andpatientswith asthma,” J fkLERGY CLINIMMUNOL 1!391:87:762-7, the legend of Fig. 1, page764, shouldread LES gradient insteadof LESresting pressure. This error does not affectthe resultsor theirinterpretation.

Bronchoprovocation committee report. American Academy of Allergy and Immunology.

Since the 1970s the BronchoprovocationCommittee of the American Academy of Allergy and Immunologyhasbeenconcernedwith the standardization of inhalatio...
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