American Thoracic Societv Guidelines for Methacholine and Exercise Challenge Testing-1999 THIS OFFICIAL STA.TEMENT OF THE AMERICAN THORACIC SOCIETY W AS ADORED BY THE ATS BOARD OF DIRECTORS, JULY 1999 I. Purpose and Scope The bronchial challenge tests chosen for review are the two II. Methacholine Challenge Testing most widely used, with enough information in the literature to A. Indications evaluate their utility. Of the two, methacholine challenge test- B. Contraindications ing is better established; a number of aspects in the exercise C. Technician Training/Qualifications challenge protocol will benefit from further evaluation. We do D. Safety not cover specific challenges with allergens, drugs, or occupa- E. Patient Preparation tional sensitizers, and recommend that such tests be performed F. Choice and Preparation of Methacholine only in laboratories with considerable experience in their tech- G. Dosing Protocols niques. For more extensive details or other challenge proce- 1. Two-Minute Tidal Breathing Dosing Protocol dures the reader is referred to previously published guidelines 2. Five-Breath Dosimeter Protocol for bronchial challenge testing (l-5) and reviews on the gen- H. Nebulizers and Dosimeters eral topic of BHR (6-9). I. Spirometry and Other End-point Measures As with other American Thoracic Society (ATS) statements J. Data Presentation on pulmonary function testing, these guidelines come out of a K. Interpretation consensus conference. The basis of discussion at the committee’s III. Exercise Challenge September 1997 meeting was a draft prepared by three members A. Indications (P.E., C.I., and R.C.). The draft was based on a comprehensive B. Contraindications and Patient Preparation Medline literature search from 1970 through 1997, augmented C. Exercise Challenge Testing by suggestions from other committee members. The final rec- D. Assessing the Response ommendations represent a consensus of the committee. For is- References sues on which unanimous agreement could not be reached, the Appendix A: Sample Methacholine Challenge Test Consent guidelines reflect both majority and minority opinions. Form The committee recommends that the guidelines be reviewed Appendix B: Sample Methacholine Challenge Pretest Ques- in 5 years and, in the meantime, encourages further research tionnaire in the areas of controversy. Appendix C: Sample Report Format Appendix D: Equipment Sources II. METHACHOLINE CHALLENGE TESTING A. Indications Methacholine challenge testing is one method of assessing air- I. PURPOSE AND SCOPE way responsiveness. Airway hyperresponsiveness is one of the This statement provides practical guidelines and suggestions features that may contribute to a diagnosis of asthma. It may for methacholine and exercise challenging testing. Specifi- vary over time, often increasing during exacerbations and de- cally, it reviews indications for these challenges, details factors creasing during treatment with antiinflammatory medications. that influence the results, presents brief step-by-step proto- Methacholine challenge testing (MCT) is most often consid- cols, outlines safety measures, describes proper patient prepa- ered when asthma is a serious possibility and traditional meth- ration and procedures, provides an algorithm for calculating ods, most notably spirometry performed before and after results, and offers guidelines for clinical interpretation of re- administration of a bronchodilator, have not established or sults. The details are important because methacholine and ex- eliminated the diagnosis. Symptoms that suggest asthma in- ercise challenge tests are, in effect, dose-response tests and clude wheezing, dyspnea, chest tightness, or cough in the fol- delivery of the dose and measurement of the response must be lowing circumstances: (I) with exposure to cold air, (2) after accurate if a valid test is to be obtained. These guidelines are exercise, (3) during respiratory infections, (4) following inhal- geared to patients who can perform good-quality spirometry ant exposures in the workplace, and (5) after exposure to al- tests; they are not appropriate for infants or preschool chil- lergens and other asthma triggers. A history of such symptoms dren. They are not intended to limit the use of alternative pro- increases the pretest probability of asthma. The optimal diag- tocols or procedures that have been established as acceptable nostic value of MCT (the highest combination of positive and methods. We do not discuss the general topic of bronchial hy- negative predictive power) occurs when the pretest probabil- perresponsiveness (BHR). ity of asthma is 30-70% (10). Methacholine challenge testing is more useful in excluding a diagnosis of asthma than in es- tablishing one because its negative predictive power is greater than its positive predictive power. Am J Respir Crit Care Med Vol 161. pp 309-329, 2000 Methacholine challenge testing is also a valuable tool in the Internet address: www.atsjournals.org evaluation of occupational asthma. Methacholine challenge 310 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161 2000 testing is sometimes used to determine the relative risk of de- airway responsiveness correlates strongly with the degree of veloping asthma, assess the severity of asthma, and assess re- baseline airway obstruction in COPD. In the presence of a sponse to asthma therapy although its clinical use in these ar- good clinical picture for asthma, if baseline spirometry shows eas has not been well established. airflow obstruction and there is a significant bronchodilator Rationale. Even asthma specialists cannot accurately pre- response (> 12% and > 0.2-L increases in either FEV, or dict MCT results in patients with an intermediate probability FVC) the diagnosis of asthma is often confirmed and MCT is of asthma (I 1). The MCT has excellent sensitivity but medio- usually unnecessary. cre positive predictive value for asthma (8). Most subjects with Spirometry quality. An acceptable-quality methacholine current asthma symptoms will have BHR. However, bronchial challenge test depends on the ability of the patients to perform hyperresponsiveness is also seen in a wide variety of other dis- acceptable spirometric maneuvers. Patients who cannot per- eases, including smoking-induced chronic airway obstruction form acceptable spirometry tests in the baseline session should (COPD), congestive heart failure (CHF), cystic fibrosis, bron- perhaps be rescheduled or be tested using an end-point mea- chitis, and allergic rhinitis (12-14). sure that is less dependent on patient effort. Because improvement in the clinical severity of asthma is Cardiovascular problems. A history of cardiovascular prob- associated with improvement in airway responsiveness (1.5, lems may also be a contraindication, depending on the prob- 16) clinical studies of asthma therapies often use change in air- lem. The additional cardiovascular stress of induced broncho- way responsiveness as an objective outcome measure (9, 17- spasm may precipitate cardiovascular events in patients with 25). Sont and colleagues have demonstrated the efficacy of a uncontrolled hypertension or recent heart attack or stroke. In- treatment program that included measures of airway hyperre- duced bronchospasm causes ventilation-perfusion mismatching activity in the management approach (26). However, we be- (31,32), which can result in arterial hypoxemia and compensa- lieve the routine use of MCT to examine patients with asthma tory changes in blood pressure, cardiac output, and heart rate in a clinical setting should await further exploration of the util- (33, 34). On the other hand, cardiac arrhythmia rates actually ity of such testing. fall during the performance of FVC maneuvers (35). Pregnancy and nursing mothers. Methacholine is a preg- B. Contraindications nancy category C drug, meaning that animal reproductive stud- The contraindications to methacholine challenge testing, sum- ies have not been performed and it is not known whether it is marized in Table 1, are all conditions that may compromise associated with fetal abnormalities. It is not known whether the quality of the test or that may subject the patient to increased methacholine is excreted in breast milk. risk or discomfort. They are identified in the pretest interview or questionnaire. If contraindications are identified, they C. Technician Training/Qualifications should be discussed with the physician who ordered the test or There is no recognized certification program for persons who the medical director of the laboratory before proceeding. perform methacholine challenge testing. The pulmonary labo- Rationale. Low FEV,. Occasional dramatic falls in FEV, ratory director is responsible for evaluating and/or verifying may occur during MCT and the risk of such events may be in- the training and qualification of the person(s) who perform the creased in individuals with low baseline lung function. Re- test. At a minimum, the technician should: duced lung function is a relative contraindication because the overall risk of serious adverse events is small, even in patients 1. Be familiar with this guideline and knowledgeable about with asthma who have severe airway obstruction (27). The specific test procedures level of lung function at which MCT is contraindicated is con- 2. Be capable of managing the equipment including set-up, troversial. A baseline FEV, of < 1.5 L or < 60% predicted in verification of proper function, maintenance, and cleaning adults is proposed as a relative contraindication