Abbreviated Methacholine Challenge

Abbreviated Methacholine Challenge How Safe Are Short Procedures? To the Editor: Increased nonspecific bronchial hyperresponsiveness to pharmacologic agents such as methacholine is a hallmark of asthma. The measurement of airway reactivity is quite sensitive, but testing is tedious and time consuming. It is not surprising to find in the literature many attempts aimed to design the shortest possible yet safe inhalation challenge protocol. While there is an abundance of such rapid protocols set for epidemiologic studies of randomized, largely healthy populations,1–3 there are only a few recommendations for short protocols that may be applicable in the population seen in a lung function referral center.4 – 6 The work of Juniper et al4 should be mentioned in particular, as it was adopted by the Canadian Thoracic Association and seemed to have gained some popularity worldwide. However, those of us who test patients in referral centers know that this issue is far from being settled, and that many centers run their own abbreviated procedures. In fact, the American Thoracic Society published an official guideline for methacholine challenge testing,7 but could not come up with an agreed-on protocol, and I am quoting: “Many different protocols have been used . . . and the committee was unable to come to a single recommendation.” Three articles have been published recently on this issue, two appeared in the European Respiratory Journal8,9 and one appeared in this journal.10 The study of Cockcroft et al10 is essentially a retrospective inspection of 1,000 tests that were performed according to the protocol recommended by Juniper et al.4 According to this study, the initial inhalation concentration can be ⬎ 0.03 mg/mL, and a fourfold rather than doubling concentration steps may be taken in most cases. The results seem very encouraging in that the probability of a severe response (ie, ⌬FEV1 ⱖ 40%) was kept to a reasonable level of 1.3% of the tested population (4.1% of all responders). We feel that the recent publication of Cockcroft et al10 warrants further discussion on four particular aspects: 1. The practice of choosing a more conservative strategy when dealing with patients rather than a randomized, largely healthy population stems from our a priori knowledge that a much larger proportion of subjects will respond to the challenge test. The clinical distribution of patients studied by us9 and by Troyanov et al8 yielded indeed 60% positive responders. The study of Cockcroft et al,10 however, yielded a disappointingly low number of positive responders (32%), close to results obtained from epidemiologic studies. 2. The algorithm suggested by Cockcroft et al10 differs from ours9 in that it critically relies on obtaining a medical history of the patient and knowing his or her medication needs. These criteria require a greater need for the attending physician and/or better technician training. They are also subjective and are prone to large variability between practicing centers. We feel that our algorithm overcomes these shortcomings by relying solely on an objective criterion (ie, baseline value of FEV1/FVC ⱖ 80%). Furthermore, this is more practical to implement in a busy clinical center, as it simplifies laboratory routines. 3. Juniper et al4 and Cockcroft et al10 suggested that in asthmatic subjects with normal baseline lung function, the initial concentration could be as high as 1 mg/mL if they are maintained on intermittent bronchodilators, and 2 mg/mL if they receive no medications. The American Thoracic Society official statement7 adopted a slightly more cautious view in recommending that only subjects “not known to have asthma and taking no asthma medications” could be started at a dose of 1 mg/mL. In our experience,9 62 of 280 subjects (22.1%) with baseline FEV1/FVC 752

ⱖ 80% had a positive response (ie, ⌬FEV1 ⱖ 20%) at an inhalation concentration of 0.5 mg/mL, 22 of them having a provocative concentration of methacholine causing a 20% fall in FEV1 ⱕ 0.25 mg/mL. While some of our patients were receiving antiasthmatic medications, it is very probable that many of these 62 patients would have had a very severe response had they been started at an initial concentration of 1 mg/mL as suggested here. Thus, we do not feel that these recommendations are safe enough. Our algorithm suggesting the use of 0.21 mg/mL as the initial concentration was found to be safe. 4. Juniper et al4 and Cockcroft et al10 further suggested a fourfold increase as compared to our tripling concentration steps. It is intuitively obvious that our algorithm is more conservative and hence safer. Cockcroft et al10 cut this risk by falling back to the doubling concentration protocol when a response of ⌬FEV1 ⱖ 5% was observed. We feel that such a small change in FEV1 falls within test variability and will impose unnecessary spurious recordings. Instead, our algorithm calls for falling back when a ⌬FEV1 ⬎ 10% is observed. In summary, both algorithms9,10 are successful in shortening the test to an average of about 30 min while keeping it as safe as the standard test (ie, 3 to 4% occurrence rate of severe responses). Our algorithm appears to be safer in our group of patients, and it is quite possible that outcome depends on patient composite. As was correctly pointed out in the editorial adjoining this publication,11 the use of methacholine challenge testing is highly recommended and abbreviated algorithms will bring about the needed wider use of it. However, a more careful look at suggested protocols is needed before the final verdict is reached. Ephraim Bar-Yishay, PhD Institute of Pulmonology, Hadassah University Hospital Jerusalem, Israel Correspondence to: Ephraim Bar-Yishay, PhD, Institute of Pulmonology, Hadassah University Hospital, PO Box 12000, Jerusalem, Israel 91120; e-mail: [email protected]

References 1 Yan K, Salome C, Woolcock AJ. Rapid method for measurement of bronchial responsiveness. Thorax 1983; 38:760 –765 2 Sears MR, Jones DT, Holdaway MD, et al. Prevalence of bronchial reactivity to inhaled methacholine in New Zealand children. Thorax 1986; 41:283–289 3 Higgins BG, Britton JR, Chinn S, et al. Comparison of histamine and methacholine for use in bronchial challenge tests in community studies. Thorax 1988; 43:605– 610 4 Juniper EF, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method; laboratory procedure and standardization. 2nd ed. Lund, Sweden: Astra Draco AB, 1994; SBN 91– 86058-29 – 0 5 Chatham M, Bleecker ER, Norman P, et al. A screening test for airways reactivity. Chest 1982; 82:15–18 6 Jorres RA, Nowak D, Kirsten D, et al. A short protocol for methacholine provocation testing adapted to the RosenthalChai dosimeter technique. Chest 1997; 111:866 – 869 7 American Thoracic Society. Guidelines for methacholine and exercise challenge testing, 1999. Am J Respir Crit Care Med 1999; 161:309 –329 8 Troyanov S, Malo JL, Cartier A, et al. Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups. Eur Respir J 2000; 16:9 –14 9 Izbicki G, Bar-Yishay E. Methacholine inhalation challenge: a simplified, shorter and cheaper approach. Eur Respir J 2001; 17:46 –51 Communications to the Editor

10 Cockcroft DW, Marciniuk DD, Hurst TS, et al. Methacholine challenge: test-shortening procedures. Chest 2001; 120:1857– 1860 11 Phillips YY, Schreiner RD. Streamlining methacholine challenge testing [editorial]. Chest 2001; 120:1763–1766 To The Editor: We thank Dr. Bar-Yishay for his interest in our article1 and the comments in his letter, and we apologize for having missed the article published in the past year2 addressing the same question in a somewhat different fashion. As outlined by Dr. Bar-Yishay, this is an important issue. Our article was not intended to review the entire issue of test-shortening procedures; rather, it was designed to look at our method alone. Our 2-min tidal breathing method,3,4 although by no means the only acceptable method for methacholine challenge, is widely used. A recurring criticism is that it is very tedious and time-consuming to administer all 9 or 10 concentrations. The guidelines for shortening the test were published ⬎ 20 years ago,4 but this publication is not routinely available. Our goals in publishing the retrospective analysis were to increase exposure to the previously published guidelines,4 and to (hopefully) offer some validation that they could be safely applied in a routine tertiary care clinical setting. Although the test-shortening wording may be a little ambiguous, the intention in our methods booklet4 was that these guidelines, particularly starting at the higher concentrations, did refer to patients not known to have asthma (as suggested by the American Thoracic Society [ATS]5). There are many different methacholine challenge methods involving differences in nebulization, inhalation pattern, and dose step-ups. The dose step-ups can range from the standard doublingdose regimen to the tripling-dose regimen recommended by Izbicki and Bar-Yishay,2 the quadrupling regimen recommended as optional by the ATS,5 to the widely variable up to 10-fold dose step-ups recommended by the American Academy of Allergy, Asthma, and Immunology bronchoprovocation committee,6 a regimen that the ATS did not recommend. Methodologic differences make comparison of data obtained by different groups difficult. It is possible to address at least some of Dr. Bar-Yishay’s points by one important methodologic difference, namely that their 2-min tidal breathing protocol utilized a nebulizer with an output of 0.34 mL/min, or 2.6-fold greater than the 0.13 mg/mL recommended for our method both by ourselves3,4 and by the ATS5; this indicates that the provocative concentrations of methacholine causing a 20% fall in FEV1 (PC20) discussed in the letter by Dr. Bar-Yishay require multiplication by a factor of 2.6 in order to be comparable to those in our article. With that background, we would like to address Dr. Bar-Yishay’s four points: 1. Dr. Bar-Yishay notes our low response rate (31.5%) compared to the 60% response rate defined as responding at 8.0 mg/mL by their method. Their PC20 of 8 mg/mL would correspond to a PC20 of approximately 20.0 mg/mL by our method. We do not have enough data to accurately address this issue. However, it is reasonable to estimate that the majority of subjects whose FEV1 fell ⬎ 10% (but ⬍ 20%) after inhaling 8 mg/mL would have a PC20 between 8 mg/mL and 16 mg/mL.7 We reexamined our data and found an additional 251 subjects who fell into this category. This gives us 566 subjects or 56.6% estimated to have a PC20 ⬍ 16 mg/mL comparable to the 60% response rate by the method of Dr. Bar-Yishay; this is also the ATS cutoff between normal and borderline.5 2. We agree that the algorithm outlined initially by Juniper et al4 and supported by ourselves relies on an accurate medical www.chestjournal.org

history, and that increased suspicion that asthma is present should result in increasing caution with a starting concentration. We continue to believe that this is as important or perhaps even more important than the objective criteria proposed by Dr. Bar-Yishay. We have a concern that it may be dangerous to rely solely on objective criteria to determine methacholine test shortening. 3. The intention of the guideline booklet was that these recommendations referred to subjects “not known to have asthma . . . ” and indeed with the rare exception, methacholine challenge tests in our laboratory are restricted to subjects not known to have asthma. Correcting Dr. Bar-Yishay’s values of 0.25 mg/mL and 0.21 mg/mL to our method, the corresponding concentrations become 0.65 mg/mL and 0.55 mg/mL, which is close to our usual starting concentration of 1.0 mg/mL (even in subjects receiving no medications). 4. As outlined, the fourfold step-up following a skipped concentration is less conservative than the threefold step-up. However, using a ⌬FEV1 of ⬍ 5% to allow a quadrupling-dose step-up seems similar to Dr. Bar-Yishay’s use of ⌬FEV1 ⬍ 10% to allow a tripling-dose step-up.2 It is unclear from the algorithm outlined for their hypothetical tripling-dose protocol what step should be taken in circumstances when the FEV1 falls ⬎ 10% but ⬍ 20%. We are pleased to see that our article has stimulated a lively discussion and thank CHEST for the opportunity to reply to these comments. Donald W. Cockcroft, MD, FCCP Darcy D. Marciniuk, MD, FCCP Thomas S. Hurst David J. Cotton, MD, FCCP Karen F. Laframboise, MD, FCCP Brian D. McNab, MD, FCCP Robert P. Skomro, MD, FCCP University of Saskatchewan Saskatoon, SK, Canada Correspondence to: Donald W. Cockcroft, MD, FCCP, Department of Medicine, University of Saskatchewan, Royal University Hospital, 103 Hospital Dr, Ellis Hall, Saskatchewan, SK, Canada S7N 0W8

References 1 Cockcroft DW, Marciniuk DD, Hurst TS, et al. Methacholine challenge: test-shortening procedures. Chest 2001; 120:1857– 1860 2 Izbicki G, Bar-Yishay E. Methacholine inhalation challenge: a shorter, cheaper and safe approach. Eur Respir J 2001; 17:46 –51 3 Cockcroft DW, Killian DN, Mellon JJA, et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977; 7:235–243 4 Juniper EF, Cockcroft DW, Hargreave FE. Histamine and methacholine inhalation tests: tidal breathing method; laboratory procedure and standardisation. Lund, Sweden: AB Draco, 1991 5 Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing, 1999. Am J Respir Crit Care Med 2000; 161:309 –329 6 Shapiro GG, Simon RA. Bronchoprovocation committee report: American Academy of Allergy and Immunology. J Allergy Clin Immunol 1992; 89:775–778 7 Jokic R, Davis EE, Cockcroft DW. Methacholine PC20 extrapolation. Chest 1998; 114:1796 –1797 CHEST / 122 / 2 / AUGUST, 2002

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